Anti-amyloid compounds containing benzofurazan

ABSTRACT

In general, among other things, compounds of Formula I are provided: 
     
       
         
         
             
             
         
       
     
     in which R 11  is e.g., 4-(pyrrolidin-1-yl)piperidin-1-yl, N-methyl-3-(pyrrolidin-1-yl)propan-1-amino, N 1 ,N 1 ,N 3 -trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino, 3-(pyrrolidin-1-ylmethyl)azetidin-1-yl, 3-(pyrrolidin-1-ylmethanon)azetidin-1-yl, or 3-(morpholin-1-ylmethyl)azetidin-1-yl; R 13  is, e.g., phenyl optionally substituted with one or more substituents; and R 12  and R 14  are each independently hydrogen or alkyl. Methods of treatment are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication 61/945,697, filed Feb. 27, 2014, which is herebyincorporated by reference in its entirety.

BACKGROUND

The build-up of amyloid proteins in living tissue, a condition known asamyloidosis, is either the cause or a major factor in the pathology ofmany so-called amyloid diseases such as Alzheimer's Parkinson's,Huntington's, and prion diseases, including non-CNS disorders such asType 2 diabetes mellitus. Historically, aggregations of protein wereclassified as amyloid if they displayed apple-green birefringence underpolarized light when stained with the dyes Congo red or Thioflavin T(ThT) (Sipe and Cohen, 2000, J. Struct. Biol. 130:88-98). Thatdefinition of amyloid has been expanded in recent years to apply to anypolypeptide which can polymerize in a cross-beta sheet conformation invitro or in vivo, regardless of sequence (Xu, 2007, Amyloid 14:119-31).Certain types of amyloidosis may occur principally in the centralnervous system, as with aggregation of beta-amyloid protein inAlzheimer's Disease, tau protein in progressive supranuclear palsy,alpha-synuclein in Parkinson's Disease, huntingtin protein inHuntington's Disease, and prion protein in Creutzfeldt-Jacob and otherprion diseases. Other types of amyloidosis are systemic in nature, aswith aggregation of transthyretin in senile systemic amyloidosis.

All of the above listed diseases are invariably fatal using currentmedical practice. In none of these diseases is there any known, widelyaccepted therapy or treatment that can halt and/or reverse theaggregation of amyloid deposits. As such there remains an urgent needfor treatments.

SUMMARY

Anti-amyloid are disclosed herein that prevent or reduce the speed ofoligomerization or aggregation of amyloid proteins. This effect isexpected to have beneficial effects in diseases impacted by amyloidosis.

In general, in an aspect, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, are provided:

in which R₁₁ is selected from the group consisting of4-(pyrrolidin-1-yl)piperidin-1-yl,N-methyl-3-(pyrrolidin-1-yl)propan-1-amino,N¹,N¹,N³-trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino,3-(pyrrolidin-1-ylmethyl)azetidin-1-yl,3-(pyrrolidin-1-ylmethanon)azetidin-1-yl,3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl,3-(morpholin-1ylmethyl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl,3-(methylsulfonamide-N-methyl)azetidin-1-yl,3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl)azetidin-1-yl; R₁₃ is selected from the groupconsisting of 3-(benzyloxy)-1-methylcyclobutan-1-ol-1-yl, oxazoleoptionally substituted with one or more of substituents A, oxadiazoleoptionally substituted with one or more of substituents A, phenyloptionally substituted with one or more of substituents A, thiopheneoptionally substituted with one or more of substituents A, thiazoleoptionally substituted with one or more of substituents A, furanoptionally substituted with one or more of substituents A, pyrazoleoptionally substituted with one or more of substituents A,N-methylpyrazole optionally substituted with one or more of substituentsA, 2-pyridine optionally substituted with one or more of substituents A,3-pyridine optionally substituted with one or more of substituents A,and 4-pyridine optionally substituted with one or more of substituentsA, where A is selected from the group consisting of alkyl, alkoxy,alkthiolyl, isopropyl, t-butyl, trifluoromethyl, chloro, cyano, CF₃O—,methanonyl, methylsulfonyl, trifluoromethylsulfonyl, amide (connected ineither direction) optionally substituted with one or more alkyl, —CH₂OH,1-ol-2,2,2-trifluoroethan-1-yl, oxetan-3-ol-3-yl, 2-ol-propan-2-yl, andcyclopropyl; and R₁₂ and R₁₄ are each independently hydrogen or alkyl.

In general, in an aspect, a compound according to the above formula or apharmaceutically acceptable salt thereof is provided, in which R₁₁ isselected from the group consisting of 4-(pyrrolidin-1-yl)piperidin-1-yl,N-methyl-3-(pyrrolidin-1-yl)propan-1-amino,N¹,N¹,N³-trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino,3-(pyrrolidin-1-ylmethyl)azetidin-1-yl,3-(pyrrolidin-1-ylmethanon)azetidin-1-yl, and3-(morpholin-1-ylmethyl)azetidin-1-yl; and R₁₃ is selected from thegroup consisting of phenyl optionally substituted with one or more ofsubstituents A, thiophene optionally substituted with one or more ofsubstituents A, thiazole optionally substituted with one or more ofsubstituents A, furan optionally substituted with one or more ofsubstituents A, pyrazole optionally substituted with one or more ofsubstituents A, N-methylpyrazole optionally substituted with one or moreof substituents A, 2-pyridine optionally substituted with one or more ofsubstituents A, 3-pyridine optionally substituted with one or more ofsubstituents A, and 4-pyridine optionally substituted with one or moreof substituents A, where A is selected from the group consisting ofalkyl, alkoxy, alkthiolyl, isopropyl, t-butyl, trifluoromethyl, chloro,cyano, CF₃O—, methanonyl, methylsulfonyl, trifluoromethylsulfonyl, amide(connected in either direction) optionally substituted with one or morealkyl, and —CH₂OH.

In general, in an aspect, a compound according to the above formula or apharmaceutically acceptable salt thereof is provided, in which R₁₁ isselected from the group consisting of3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl,3-(morpholin-1ylmethyl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl,3-(methylsulfonamide-N-methyl)azetidin-1-yl,3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl)azetidin-1-yl; and R₁₃ is selected from thegroup consisting of 3-(benzyloxy)-1-methylcyclobutan-1-ol-1-yl, oxazoleoptionally substituted with one or more of substituents A, oxadiazoleoptionally substituted with one or more of substituents A, and3-pyridine optionally substituted with one or more of substituents A,where A is selected from the group consisting of1-ol-2,2,2-trifluoroethan-1-yl, oxetan-3-ol-3-yl, 2-ol-propan-2-yl, andcyclopropyl.

In general, in an aspect, a compound according to the above formula or apharmaceutically acceptable salt thereof is provided, in which R₁₃ isselected from the group consisting of 5-(2-ol-propan-2-yl)oxadizol-3-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-5-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-2-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)thiazol-2-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-6-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)-pyridin-6-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-2-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-3-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)thiophen-2-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)thiophen-3-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-5-yl,3-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-2-yl,3-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-6-yl, and2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl.

In general, in an aspect, a compound according to the above formula or apharmaceutically acceptable salt thereof is provided, in which R₁₁ is3-(morpholin-1-ylmethyl)azetidin-1-yl and R₁₃ is selected from the groupconsisting of 2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl and5-(2-ol-propan-2-yl)oxadizol-3-yl.

In general, in an aspect, methods useful in the treatment of amyloidosisare provided. The methods include administering to a subject atherapeutic compound of the present invention which inhibits amyloidaggregation or oligomerization. The amyloidosis can be Alzheimer'sdisease, progressive supranuclear palsy, frontotemporal dementia,Parkinson's disease, Huntington's disease, prion disease, senilesystemic amyloidosis, type 2 diabetes mellitus, or some other systemicor central nervous system amyloidosis.

In general, in an aspect, pharmaceutical compositions for treatingamyloidosis are provided. The pharmaceutical compositions include atherapeutic compound of the present invention in an amount effective toinhibit amyloid aggregation, and a pharmaceutically acceptable excipientor vehicle. In some implementations the amount effective is betweenabout 0.0003 to about 50 mg/kg of body weight of the person in needthereof.

In accordance with the above, the present invention is also directed topharmaceutically acceptable salts, stereoisomers, polymorphs,metabolites, analogues, and pro-drugs of the compounds, and to anycombination thereof.

With the foregoing and other advantages and features of the inventionthat will become hereafter apparent, the nature of the invention may bemore clearly understood by reference to the following detaileddescription of the invention and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a beta-amyloid aggregation assay for a compound describedherein.

FIG. 2 shows a beta-amyloid aggregation assay for a compound describedherein.

FIG. 3 shows a tau aggregation assay for a compound described herein.

FIG. 4 shows a tau aggregation assay for a compound described herein.

FIG. 5 shows a tau aggregation assay for a compound described herein.

FIG. 6 shows a tau aggregation assay for a compound described herein.

FIG. 7 shows a tau aggregation assay for a compound described herein.

FIG. 8 shows a biotinylated beta-amyloid oligomerization assay for acompound described herein.

DESCRIPTION

All patents, patent applications, and other publications referred toherein are hereby incorporated by reference in their entireties.

In one embodiment, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, are provided:

in which R₁₁ is selected from the group consisting of4-(pyrrolidin-1-yl)piperidin-1-yl,N-methyl-3-(pyrrolidin-1-yl)propan-1-amino,N¹,N¹,N³-trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino,3-(pyrrolidin-1-ylmethyl)azetidin-1-yl,3-(pyrrolidin-1-ylmethanon)azetidin-1-yl,3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl,3-(morpholin-1-ylmethyl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl,3-(methylsulfonamide-N-methyl)azetidin-1-yl,3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl)azetidin-1-yl; R₁₃ is selected from the groupconsisting of 3-(benzyloxy)-1-methylcyclobutan-1-ol-1-yl, oxazoleoptionally substituted with one or more of substituents A, oxadiazoleoptionally substituted with one or more of substituents A, phenyloptionally substituted with one or more of substituents A, thiopheneoptionally substituted with one or more of substituents A, thiazoleoptionally substituted with one or more of substituents A, furanoptionally substituted with one or more of substituents A, pyrazoleoptionally substituted with one or more of substituents A,N-methylpyrazole optionally substituted with one or more of substituentsA, 2-pyridine optionally substituted with one or more of substituents A,3-pyridine optionally substituted with one or more of substituents A,and 4-pyridine optionally substituted with one or more of substituentsA, where A is selected from the group consisting of alkyl, alkoxy,alkthiolyl, isopropyl, t-butyl, trifluoromethyl, chloro, cyano, CF₃O—,methanonyl, methylsulfonyl, trifluoromethylsulfonyl, amide (connected ineither direction) optionally substituted with one or more alkyl, —CH₂OH,1-ol-2,2,2-trifluoroethan-1-yl, oxetan-3-ol-3-yl, 2-ol-propan-2-yl, andcyclopropyl; and R₁₂ and R₁₄ are each independently hydrogen or alkyl.

In one embodiment, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, are provided:

in which R₁₁ is selected from the group consisting of4-(pyrrolidin-1-yl)piperidin-1-yl,N-methyl-3-(pyrrolidin-1-yl)propan-1-amino,N¹,N¹,N³-trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino,3-(pyrrolidin-1-ylmethyl)azetidin-1-yl,3-(pyrrolidin-1-ylmethanon)azetidin-1-yl, and3-(morpholin-1-ylmethyl)azetidin-1-yl; R₁₃ is selected from the groupconsisting of phenyl optionally substituted with one or more ofsubstituents A, thiophene optionally substituted with one or more ofsubstituents A, thiazole optionally substituted with one or more ofsubstituents A, furan optionally substituted with one or more ofsubstituents A, pyrazole optionally substituted with one or more ofsubstituents A, N-methylpyrazole optionally substituted with one or moreof substituents A, 2-pyridine optionally substituted with one or more ofsubstituents A, 3-pyridine optionally substituted with one or more ofsubstituents A, and 4-pyridine optionally substituted with one or moreof substituents A, where A is selected from the group consisting ofalkyl, alkoxy, alkthiolyl, isopropyl, t-butyl, trifluoromethyl, chloro,cyano, CF₃O—, methanonyl, methylsulfonyl, trifluoromethylsulfonyl, amide(connected in either direction) optionally substituted with one or morealkyl, and —CH₂OH; and R₁₂ and R₁₄ are each independently hydrogen oralkyl.

In one embodiment, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, are provided:

in which R₁₁ is selected from the group consisting of3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl,3-(morpholin-1-ylmethyl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl,3-(methylsulfonamide-N-methyl)azetidin-1-yl,3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl)azetidin-1-yl; R₁₂ and R₁₄ are eachindependently hydrogen or alkyl; and R₁₃ is selected from the groupconsisting of 3-(benzyloxy)-1-methylcyclobutan-1-ol-1-yl, oxazoleoptionally substituted with one or more of substituents A, oxadiazoleoptionally substituted with one or more of substituents A, and3-pyridine optionally substituted with one or more of substituents A,where A is selected from the group consisting of1-ol-2,2,2-trifluoroethan-1-yl, oxetan-3-ol-3-yl, 2-ol-propan-2-yl, andcyclopropyl.

In one embodiment, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, are provided:

in which R₁₁ is selected from the group consisting of3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl,3-(methylsulfonamide-N-methyl)azetidin-1-yl,3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl)azetidin-1-yl; R₁₂ and R₁₄ are eachindependently hydrogen or alkyl; and R₁₃ is selected from the groupconsisting of 5-(2-ol-propan-2-yl)oxadizol-3-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-5-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-2-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)thiazol-2-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-6-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)-pyridin-6-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-2-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-3-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)thiophen-2-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)thiophen-3-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-5-yl,3-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-2-yl,3-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-6-yl, and2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl.

In one embodiment, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, are provided:

in which R₁₁ is 3-(morpholin-1-ylmethyl)azetidin-1-yl; R₁₂ and R₁₄ areeach independently hydrogen or alkyl; and R₁₃ is selected from the groupconsisting of 2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl and5-(2-ol-propan-2-yl)oxadizol-3-yl.

In one embodiment, a method of treatment of an amyloid disease in asubject is provided, comprising administering a therapeuticallyeffective amount of a compound of the present invention to the subject.In some embodiments, the amyloid disease is Alzheimer's disease. In someembodiments, the amyloid disease is Parkinson's disease. In someembodiments, the amyloid disease is Huntington's disease. In someembodiments, the amyloid disease is frontotemporal dementia. In someembodiments, the amyloid disease is progressive supranuclear palsy. Insome embodiments, the amyloid disease is type 2 diabetes mellitus.

13. A method for treating a condition which is a member selected fromloss of memory, loss of cognition and a combination thereof, said methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of any of claims 1-5.

In one embodiment, a pharmaceutical composition is provided comprising acompound of the present invention and a pharmaceutically acceptablecarrier.

In one embodiment, a method for treating a condition which is a memberselected from loss of memory, loss of cognition and a combinationthereof, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound disclosedherein. In some embodiments, said condition is associated withAlzheimer's disease. In some embodiments, said condition is associatedwith progressive supranuclear palsy. In some embodiments, thetherapeutically effective amount is a total daily dose of from about0.0003 to about 50 mg/kg of body weight of the subject.

It is believed that compounds of the present invention inhibit theaggregation of amyloid protein. Data supportive of this conclusion canbe found in the Examples below.

DEFINITIONS

Unless otherwise defined, terms as used in the specification refer tothe following definitions, as detailed below.

The terms “administration” or “administering” compound should beunderstood to mean providing a compound of the present invention to anindividual in a form that can be introduced into that individual's bodyin an amount effective for prophylaxis, treatment, or diagnosis, asapplicable. Such forms may include e.g., oral dosage forms, injectabledosage forms, transdermal dosage forms, inhalation dosage forms, andrectal dosage forms.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy. The term “alkthiolyl” as used herein means the analogous groupcontaining sulfur rather than oxygen.

The term “alkyl” as used herein means a straight or branched chainhydrocarbon containing from 1 to 20 carbon atoms, preferably from 1 to10 carbon atoms, more preferably 1, 2, 3, 4, 5, or 6 carbons.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “carbonyl” as used herein means a —C(═O)— group.

The term “carboxy” as used herein means a —COOH group, which may beprotected as an ester group: —COO-alkyl.

The term “fluoro” as used herein means —F.

The term “halo” or “halogen” as used herein means Cl, Br, I, or F.

The term “heteroaryl”, as used herein, refers to an aromatic ringcontaining one or more heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a tautomer thereof. Such rings can be monocyclicor bicyclic as further described herein. Heteroaryl rings are connectedto a parent molecular moiety through a carbon or nitrogen atom.

The terms “heteroaryl” or “5- or 6-membered heteroaryl ring”, as usedherein, refer to 5- or 6-membered aromatic rings containing 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or a tautomer thereof. Examples of such rings include, but are notlimited to, a ring wherein one carbon is replaced with an O or atom;one, two, or three N atoms arranged in a suitable manner to provide anaromatic ring; or a ring wherein two carbon atoms in the ring arereplaced with one O or S atom and one N atom. Such rings can include,but are not limited to, a six-membered aromatic ring wherein one to fourof the ring carbon atoms are replaced by nitrogen atoms, five-memberedrings containing a sulfur, oxygen, or nitrogen in the ring; fivemembered rings containing one to four nitrogen atoms; and five memberedrings containing an oxygen or sulfur and one to three nitrogen atoms.Representative examples of 5- to 6-membered heteroaryl rings include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl,thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl,[1,3,5]triazinyl, [1,2,3]triazolyl, and [1,2,4]triazolyl.

Heteroaryl groups of the invention can be substituted with hydrogen oralkyl. Monocyclic heteroaryl or 5- or 6-membered heteroaryl rings aresubstituted with 0, 1, 2, 3, 4, or 5 substituents. Heteroaryl groups ofthe present invention may be present as tautomers.

The term “hydroxy” as used herein means an —OH group.

Unless otherwise indicated, the term “prodrug” encompassespharmaceutically acceptable esters, carbonates, thiocarbonates, N-acylderivatives, N-acyloxyalkyl derivatives, quaternary derivatives oftertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates,phosphate esters, metal salts and sulfonate esters of compoundsdisclosed herein. Examples of prodrugs include compounds that comprise abiohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzablecarbamate, biohydrolyzable carbonate, biohydrolyzable ester,biohydrolyzable phosphate, or biohydrolyzable ureide analog). Prodrugsof compounds disclosed herein are readily envisioned and prepared bythose of ordinary skill in the art. See, e.g., Design of Prodrugs,Bundgaard, A. Ed., Elseview, 1985; Bundgaard, hours, “Design andApplication of Prodrugs,” A Textbook of Drug Design and Development,Krosgaard-Larsen and hours. Bundgaard, Ed., 1991, Chapter 5, p. 113-191;and Bundgaard, hours, Advanced Drug Delivery Review, 1992, 8, 1-38.

Unless otherwise indicated, the term “protecting group” or “protectivegroup,” when used to refer to part of a molecule subjected to a chemicalreaction, means a chemical moiety that is not reactive under theconditions of that chemical reaction, and which may be removed toprovide a moiety that is reactive under those conditions. Protectinggroups are well known in the art. See, e.g., Greene, T. W. and Wuts, P.G. M., Protective Groups in Organic Synthesis (3 rd ed., John Wiley &Sons: 1999); Larock, R. C., Comprehensive Organic Transformations (2 nded., John Wiley & Sons: 1999). Some examples include benzyl,diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl,and pthalimido. Protecting groups include, for example, nitrogenprotecting groups and hydroxy-protecting groups.

The term “sulfonyl” as used herein means a —S(O)₂— group.

The term “thioalkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of thioalkoxy include, but are no limited to,methylthio, ethylthio, and propylthio.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. Pharmaceutically acceptable salt(s) are well-known in the art.For clarity, the term “pharmaceutically acceptable salts” as used hereingenerally refers to salts prepared from pharmaceutically acceptablenon-toxic acids or bases including inorganic acids and bases and organicacids and bases. Suitable pharmaceutically acceptable base additionsalts include metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include inorganic and organic acids such as acetic,alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include hydrochloride and mesylate salts. Others arewell-known in the art. See, e.g., Remington's Pharmaceutical Sciences,18 th ed. (Mack Publishing, Easton Pa.: 1990) and Remington: The Scienceand Practice of Pharmacy, 19th ed. (Mack Publishing, Easton Pa.: 1995).The preparation and use of acid addition salts, carboxylate salts, aminoacid addition salts, and zwitterion salts of compounds of the presentinvention may also be considered pharmaceutically acceptable if theyare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, are commensuratewith a reasonable benefit/risk ratio, and are effective for theirintended use. Such salts may also include various solvates and hydratesof the compound of the present invention.

Certain compounds of the present invention may be isotopically labelled,e.g., with various isotopes of carbon, fluorine, or iodine, asapplicable when the compound in question contains at least one suchatom. In preferred embodiments, methods of diagnosis of the presentinvention comprise administration of such an isotopically labelledcompound.

Certain compounds of the present invention may exist as stereoisomerswherein, asymmetric or chiral centers are present. These stereoisomersare “R” or “S” depending on the configuration of substituents around thechiral carbon atom. The terms “R” and “S” used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof and these arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Certain compounds of the present invention may exist as cis or transisomers, wherein substituents on a ring may attach in such a manner thatthey are on the same side of the ring (cis) relative to each other, oron opposite sides of the ring relative to each other (trans). Suchmethods are well known to those of ordinary skill in the art, and mayinclude separation of isomers by recrystallization or chromatography. Itshould be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention.

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.For example, the terms “pyridine” and “pyridyl” are accorded the samemeaning when used to describe a moiety attached to other chemicalmoieties. Thus, for example, the two phrases “XOH, wherein X is pyridyl”and “XOH, wherein X is pyridine” are accorded the same meaning, andencompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

The term “pharmaceutically acceptable excipient”, as used herein, meansa non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

Unless otherwise indicated, the terms “prevent,” “preventing” and“prevention” contemplate an action that occurs before a patient beginsto suffer from the specified disease or disorder, which inhibits orreduces the severity of the disease or disorder or of one or more of itssymptoms. The terms encompass prophylaxis.

Unless otherwise indicated, a “prophylactically effective amount” of acompound is an amount sufficient to prevent a disease or condition, orone or more symptoms associated with the disease or condition, orprevent its recurrence. A prophylactically effective amount of acompound is an amount of therapeutic agent, alone or in combination withother agents, which provides a prophylactic benefit in the prevention ofthe disease. The term “prophylactically effective amount” can encompassan amount that improves overall prophylaxis or enhances the prophylacticefficacy of another prophylactic agent.

Unless otherwise indicated, a “diagnostically effective amount” of acompound is an amount sufficient to diagnose a disease or condition. Ingeneral, administration of a compound for diagnostic purposes does notcontinue for as long as a therapeutic use of a compound, and could beadministered only once if such is sufficient to produce the diagnosis.

Unless otherwise indicated, a “therapeutically effective amount” of acompound is an amount sufficient to treat a disease or condition, or oneor more symptoms associated with the disease or condition. Theappropriate amount depends upon, among other things, the stage of thedisease or condition; the age of the patient; the weight of the patient;the bioavailability of the compound with respect to a target tissue; theconcentration of compound required in vivo to result in a beneficialeffect relative to control as measured by behavior, motor, biochemical,anatomical, or other readouts; or the concentration of compound requiredto result in a pharmacodynamic effect upon a target amyloid protein atthe target tissue. In some embodiments, the disease is a neurologicdisorder, the target amyloid protein is beta-amyloid protein, and thetarget tissue is brain. In some embodiments, the disease is a neurologicdisorder, the target amyloid protein is tau protein, and the targettissue is brain. In some embodiments, the diseases is a neurologicdisorder, both beta-amyloid and tau protein are target amyloid proteins,and the target tissue is brain. In some embodiments, the disease is ametabolic disorder such as Type 2 diabetes, the target amyloid proteinis amylin, and the target tissue is pancreas. In the absence of clinicaldata, the concentration of compound required to result in apharmacodynamic effect may be estimated in vitro by correlating thecompound concentration required for reduction in oligomerization oraggregation in vitro as against a concentration of a target amyloidprotein in vitro with the concentration of the target amyloid proteinexpected to be found in the target tissue, such that the requiredconcentration in vivo is approximately equal to (in vitro compoundconcentration * in vivo amyloid concentration/in vitro amyloidconcentration); from which the therapeutically effective amount can befurther estimated based on animal-derived pharmacokinetic informationsuch as bioavailability, blood-brain barrier penetrance, and proteinbinding.

The term “subject” is intended to include living organisms in whichdisease may occur. Examples of subjects include humans, monkeys, cows,sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.

The term “substantially pure” means that the isolated material is atleast 90% pure, preferably 95% pure, even more preferably 99% pure asassayed by analytical techniques known in the art.

The pharmaceutical compositions can be formulated for oraladministration in solid or liquid form, for parenteral intravenous,subcutaneous, intramuscular, intraperitoneal, intra-arterial, orintradermal injection, for or for vaginal, nasal, topical, or rectaladministration. Pharmaceutical compositions of the present inventionsuitable for oral administration can be presented as discrete dosageforms, e.g., tablets, chewable tablets, caplets, capsules, liquids, andflavored syrups. Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Parenteral dosage forms can be administered to patients by variousroutes including subcutaneous, intravenous (including bolus injection),intramuscular, and intraarterial. Because their administration typicallybypasses patients' natural defenses against contaminants, parenteraldosage forms are specifically sterile or capable of being sterilizedprior to administration to a patient. Examples of parenteral dosageforms include solutions ready for injection, dry products ready to bedissolved or suspended in a pharmaceutically acceptable vehicle forinjection, suspensions ready for injection, and emulsions.Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable medium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols. The solid dosageforms of tablets, dragees, capsules, pills, and granules can be preparedwith coatings and shells such as enteric coatings and other coatingswell known in the pharmaceutical formulating art. They may optionallycontain opacifying agents and can also be of a composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract in a delayed manner Examples of materialswhich can be useful for delaying release of the active agent can includepolymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents. Dosage forms for topical or transdermaladministration of a compound of this invention include ointments,pastes, creams, lotions, gels, powders, solutions, sprays, inhalants orpatches. A desired compound of the invention is admixed under sterileconditions with a pharmaceutically acceptable carrier and any neededpreservatives or buffers as may be required. Ophthalmic formulation, eardrops, eye ointments, powders and solutions are also contemplated asbeing within the scope of this invention. The ointments, pastes, creamsand gels may contain, in addition to an active compound of thisinvention, animal and vegetable fats, oils, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together. Methods toform liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.,(1976), p 33 et seq.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

An effective amount of one of the compounds of the invention can beemployed in pure form or, where such forms exist, in pharmaceuticallyacceptable salt form. Alternatively, the compound can be administered asa pharmaceutical composition containing the compound of interest incombination with one or more pharmaceutically acceptable carriers. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; the risk/benefit ratio; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of the present invention asadministered to a human or lower animal may range from about 0.0003 toabout 50 mg/kg of body weight. For purposes of oral administration, morepreferable doses can be in the range of from about 0.0003 to about 5mg/kg body weight. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration; consequently, singledose compositions may contain such amounts or submultiples thereof tomake up the daily dose. For oral administration, the compositions of theinvention are preferably provided in the form of tablets containingabout 1.0, about 5.0, about 10.0, about 15.0, about 25.0, about 50.0,about 100, about 250, or about 500 milligrams of the active ingredient.

EXAMPLES Synthetic Methods

Unless otherwise stated, compound IDs denoted by “TRV-” that containchiral centers found in

groups were synthesized and tested as racemic mixtures with respect tothat respective chiral center. Compounds containing substitutedpyrrolidines are intended to encompass both R and S enantiomers eitheras substantially entantiomerically pure, or as racemates.

The following synthetic schemes and written procedures were used tosynthesize the compounds described herein:

4,6-dibromobenzo[c][1,2,5]oxadiazole 4 (0.9678 g, 3.48 mmol) andbenzylamine (1.9 mL, 17.4 mmol) were dissolved in DMSO (10.5 mL) underargon and stirred in a sealed tube for 3 days, after which time, thetube was heated to 60° C. for 12 hours. Upon cooling to roomtemperature, the reaction was diluted with water and extracted withEtOAc. The combined organic layers were washed with H₂O (5×), 1 N HCl(aq), saturated NaHCO₃ (aq) and brine before drying with Na₂SO₄,filtering and concentrating. The dark solid was recrystallized from EtOHand the dark crystals were collected by filtration and dried to afford0.4516 g (43% yield) ofN-benzyl-6-bromobenzo[c][1,2,5]oxadiazol-4-amine. This material (0.1980g, 0.651 mmol), benzoylpiperazine hydrochloride (0.1771 g, 0.781 mmol)and Cs₂CO₃ (0.6353 g, 1.95 mmol) were added to a tube. The tube wasevacuated and purged with argon (3×). Toluene (2 mL) and NMP (1.2 mL)were then added to the tube and its contents were degassed for 15minutes, at which point Pd₂(dba)₃ (0.0119 g, 0.0130 mmol) and BINAP(0.0162 g, 0.026 mmol) were quickly added, the tube was sealed andheated at 100° C. overnight. Upon cooling to room temperature, thereaction was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with H₂O (5×), 1 N HCl (aq), saturated NaHCO₃(aq) and brine before drying with Na₂SO₄, filtering and concentrating.The crude material was purified via chromatography (40% EtOAc/Hexanes)to give 0.188 g (70% yield) of TRV-1256. ¹H NMR (500 MHz, CDCl₃)δ=7.46-7.43 (m, 5H), 7.39-7.36 (m, 4H), 7.34-7.31 (m, 1H), 6.13 (d,J=1.0 Hz, 1H), 5.88 (s, 1H), 5.32 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz,2H), 3.90 (br s, 2H), 3.58 (br s, 2H), 3.29 (br s, 2H), 3.15 (br s, 2H).

N-benzyl-6-bromobenzo[c][1,2,5]oxadiazol-4-amine (0.2235 g, 0.735 mmol)and 3-acetylbenzeneboronic acid (0.1566 g, 0.955 mmol) were added to atube. The tube was evacuated and purged with argon (3×). 2 M Na₂CO₃ (1.1mL, 2.21 mmol) and DME (1.6 mL) were added and the solution was degassedfor 15 minutes. Pd(PPh₃)₄ (0.0425 g, 0.0368 mmol) was quickly added andthe tube was heated at 100° C. overnight. Upon cooling to roomtemperature, the reaction was diluted with water and extracted withEtOAc. The combined organic layers were washed with H₂O (5×), saturatedNaHCO₃ (aq) and brine before drying with Na₂SO₄, filtering andconcentrating. The crude material was dissolved in methanol (15 mL) andcooled to 0° C. NaBH₄ (0.0556 g, 1.47 mmol) was added and the mixturewas stirred at 0° C. for 3 hours. The reaction mixture was quenched withsaturated NaHCO₃. This thick mixture was diluted with water andextracted with DCM (5×). The extracts were then dried (Na₂SO₄), filteredand concentrated. The crude material was purified via chromatography(30% EtOAc/Hexane) to afford 0.1412 g (56% yield) of TRV-1259. ¹H NMR(500 MHz, CDCl₃) δ=7.47 (s, 1H), 7.46-7.38 (m, 7H), 7.36-7.33 (m, 1H),7.18 (s, 1H), 6.36 (s, 1H), 5.44 (t, J=5.5 Hz, 1H), 4.99-4.95 (m, 1H),4.57 (d, J-5.5 Hz, 2H), 1.88 (d, J=3.5 Hz, 1H), 1.54 (d, J=7.0 Hz, 3H)

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3122 g, 1.12 mmol), pyrrolidine(0.10 mL, 1.12 mmol) and DIPEA (0.20 mL, 1.12 mmol) were dissolved inNMP (2 mL) under argon and stirred in a sealed tube at 100° C.overnight. Upon cooling to room temperature, the reaction was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with H₂O (5×), 1 N HCl(aq), saturated NaHCO₃ (aq) and brinebefore drying with Na₂SO₄, filtering and concentrating to give the crude6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.2247 g, 75%yield). The crude material (0.1964 g, 0.73 mmol) and3-acetylbenzeneboronic acid (0.1558 g, 0.95 mmol) were added to a tube.The tube was evacuated and purged with argon (3×). 2 M Na₂CO₃ (1.1 mL,2.21 mmol) and DME (1.6 mL) were added and the solution was degassed for15 minutes. Pd(PPh₃)₄ (0.0422 g, 0.0365 mmol) was quickly added and thetube was heated at 100° C. overnight. Upon cooling to room temperature,the reaction was diluted with water and extracted with EtOAc. Thecombined organic layers were washed with H₂O (5×), saturated NaHCO₃ (aq)and brine before drying with Na₂SO₄, filtering and concentrating. Thecrude material was dissolved in methanol (12 mL) and cooled to 0° C.NaBH₄ (0.0552 g, 1.46 mmol) was added and the mixture was stirred at 0°C. for 3 hours. The reaction mixture was quenched with saturated NaHCO₃.This thick mixture was diluted with water and extracted with DCM (5×).The extracts were then dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified via chromatography (30% EtOAc/Hexane) toafford 0.2029 g (90% yield, over 2 steps) of TRV-1310. ¹H NMR (CDCl₃)δ=7.65 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.07 (s, 1H),6.11 (s, 1H), 5.00-4.99 (m, 1H), 3.81 (s, 4H), 2.12-2.09 (m, 4H), 1.92(d, J=3.0 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.5607 g, 2.0 mmol),N-methyl-1-phenylmethanamine (0.28 mL, 2.2 mmol) and DIPEA (0.52 mL, 3.0mmol) were dissolved in NMP (3 mL) under argon and stirred in a sealedtube at 100° C. overnight. Upon cooling to room temperature, thereaction was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with H₂O (5×), 1 N HCl (aq), saturated NaHCO₃(aq) and brine before drying with Na₂SO₄, filtering and concentrating togive the crude material(N-benzyl-6-bromo-N-methylbenzo[c][1,2,5]oxadiazol-4-amine) as an oil.This crude material and 3-acetylbenzeneboronic acid (0.4263 g, 2.6 mmol)were added to a tube. The tube was evacuated and purged with argon (3×).2 M Na₂CO₃ (3.0 mL, 6.0 mmol) and DME (4.5 mL) were added and thesolution was degassed for 15 minutes. Pd(PPh₃)₄ (0.1156 g, 0.10 mmol)was quickly added and the tube was heated at 100° C. overnight. Uponcooling to room temperature, the reaction was diluted with water andextracted with EtOAc. The combined organic layers were washed with H₂O(5×), saturated NaHCO₃ (aq) and brine before drying with Na₂SO₄,filtering and concentrating. The crude material was dissolved inmethanol (33 mL) and cooled to 0° C. NaBH₄ (0.1513 g, 4.0 mmol) wasadded and the mixture was stirred at 0° C. for 3 hours. The reactionmixture was quenched with saturated NaHCO₃. This thick mixture wasdiluted with water and extracted with DCM (5×). The extracts were thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (30% EtOAc/Hexane) to afford 0.4843 g (67%yield, over 3 steps) of TRV-1358 as yellow oil. ¹H NMR (CDCl₃, 500 MHz)δ=7.60 (s, 1H), 7.51 (dt, J=6.5, 2.0 Hz, 1H), 7.47-7.42 (m, 2H),7.35-7.32 (m, 2H), 7.29-7.28 (m, 3H), 7.24 (s, 1H), 6.37 (s, 1H), 5.16(s, 2H), 5.01-4.96 (m, 1H), 3.22 (s, 3H), 1.85 (d, J=3.5 Hz, 1H), 1.55(d, J=6.5 Hz, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3765 g, 1.35 mmol), ethylpyrrolidine-2-carboxylate hydro chloride (0.2677 g, 1.49 mmol) and DIPEA(0.59 mL, 3.38 mmol) were dissolved in NMP (1.8 mL) under argon andstirred in a sealed tube at 100° C. overnight. Upon cooling to roomtemperature, the reaction was diluted with water and extracted withEtOAc. The combined organic layers were washed with H₂O (5×), 1 N HCl(aq), saturated NaHCO₃ (aq) and brine before drying with Na₂SO₄,filtering and concentrating to give 0.1756 g (38% yield) of crudematerial. This crude material and 3-acetylbenzeneboronic acid (0.1099 g,0.67 mmol) were added to a tube. The tube was evacuated and purged withargon (3×). 2 M Na₂CO₃ (0.8 mL, 1.55 mmol) and DME (1.2 mL) were addedand the solution was degassed for 15 minutes. Pd(PPh₃)₄ (0.0298 g,0.0258 mmol) was quickly added and the tube was heated at 100° C.overnight. Upon cooling to room temperature, the reaction was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with H₂O (5×), saturated NaHCO₃ (aq) and brine before drying withNa₂SO₄, filtering and concentrating. The crude material was thendissolved in DCM (0.3 mL) and toluene (1.6 mL) and this solution wascooled to 0° C. DIBAL (1.7 mL of a 1.0 M solution in hexane) was addeddropwise and the reaction was allowed to stir overnight. Another 1.5 eqof DIBAL (0.8 mL) was added at 0° C. and the reaction was stirred for anadditional 24 hours. The mixture was quenched with a saturated solutionof sodium potassium tartrate and extracted with ethyl acetate. Thecombined extracts were washed with H₂O and brine, dried with Na₂SO₄,filtered and concentrated. The crude material was purified via 60%EtOAc/hexane column to afford 0.1224 (70% yield, 2 steps) of TRV-1359 asorange solid. ¹H NMR (CDCl₃, 500 MHz) δ=7.64 (s, 1H), 7.54 (dt, J=6.5,2.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.14 (s, 1H), 6.26 (s, 1H), 5.00-4.99(br s, 1H), 4.74 (br s, 1H), 3.87-3.83 (m, 1H), 3.80-3.77 (m, 1H),3.69-3.64 (m, 1H), 3.54-3.50 (m, 1H), 2.21-2.11 (m, 4H), 1.92-1.86 (m,2H), 1.56 (d, J=6.5 Hz, 3H)

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.5385 g, 1.94 mmol), morpholine(0.17 mL, 1.94 mmol) and DIPEA (0.34 mL, 1.94 mmol) were dissolved inNMP (2.5 mL) under argon and stirred in a sealed tube at 100° C.overnight. Upon cooling to room temperature, the reaction was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with H₂O (5×), 1 N HCl (aq), saturated NaHCO₃ (aq) and brinebefore drying with Na₂SO₄, filtering and concentrating to give 0.5360 g(97% yield) of brown solid. This crude material (0.5002 g, 1.76 mmol)and 3-formylphenylboronic acid (0.3434 g, 2.29 mmol) were added to atube. The tube was evacuated and purged with argon (3×). 2 M Na₂CO₃ (2.6mL, 5.3 mmol) and DME (3.9 mL) were added and the solution was degassedfor 15 minutes. Pd(PPh₃)₄ (0.1040 g, 0.09 mmol) was quickly added andthe tube was heated at 100° C. overnight. Upon cooling to roomtemperature, the reaction was diluted with water and extracted with DCM.The combined organic layers were washed with H₂O (5×), saturated NaHCO₃(aq) and brine before drying with Na₂SO₄, filtering and concentrating.This crude material was then dissolved in THF (1.8 mL) and cooled to 0°C. CF₃TMS (0.3003 g, 2.11 mmol) was added followed by TBAF (0.18 mL,0.18 mmol) at 0° C. After the addition was complete, the ice bath wasremoved and the reaction was stirred at room temperature for severalhours, at which point, an additional 2 eq of CF₃TMS (0.52 mL) was addedalong with 0.1 eq of TBAF (0.18 mL) at 0° C. Once again warmed to roomtemperature and stirred for 2 hours. To this mixture was then added TBAF(7.6 mL, 7.6 mmol) at 0° C. and the reaction was stirred overnight. Thereaction was quenched with brine and extracted with EtOAc. The combinedextracts were washed with H₂O (4×), brine, dried (Na₂SO₄), filtered andconcentrated. Purification via flash chromatography (30% EtOAc/hexane)afford 0.2303 g (34% yield, over 3 steps) of TRV-1360 as yellow solid.¹H NMR (CDCl₃, 500 MHz) δ=7.74 (s, 1H), 7.67-7.65 (m, 1H), 7.57-7.52 (m,2H), 7.40 (s, 1H), 6.58 (s, 1H), 5.17-5.12 (m, 1H), 3.97 (t, J=5.0 Hz,4H), 3.65 (t, J=5.0 Hz, 4H), 2.75 (d, J=4.5 Hz, 1H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.4244 g, 1.58mmol) and 3-formylphenylboronic acid (0.3149 g, 2.1 mmol) were added toa tube. The tube was evacuated and purged with argon (3×). 2 M Na₂CO₃(2.4 mL, 4.7 mmol) and DME (3.6 mL) were added and the solution wasdegassed for 15 minutes. Pd(PPh₃)₄ (0.0924 g, 0.08 mmol) was quicklyadded and the tube was heated at 100° C. overnight. Upon cooling to roomtemperature, the reaction was diluted with water and extracted withethyl acetate. The combined organic layers were washed with H₂O (5×),saturated NaHCO₃ (aq) and brine before drying with Na₂SO₄, filtering andconcentrating. This crude material was then dissolved in THF (1.6 mL)and cooled to 0° C. CF₃TMS (0.2702 g, 1.9 mmol) was added followed byTBAF (0.16 mL, 0.16 mmol) at 0° C. After the addition was complete, theice bath was removed and the reaction was stirred at room temperaturefor several hours, at which point, an additional 2 eq of CF₃TMS (0.47mL) was added along with 0.1 eq of TBAF (0.16 mL) at 0° C. Once againwarmed to room temperature and stirred for 2 hours. To this mixture wasthen added TBAF (7.0 mL, 7.0 mmol) at 0° C. and the reaction was stirredovernight. The reaction was quenched with brine and extracted withEtOAc. The combined extracts were washed with H₂O (4×), brine, dried(Na₂SO₄), filtered and concentrated. Purification via flashchromatography (20% EtOAc/hexane) afford 0.2749 g (48% yield, over 3steps) of TRV-1361 as orange solid. ¹H NMR (CDCl₃, 500 MHz) δ=7.74 (s,1H), 7.68 (dt, J=7.0, 1.5 Hz, 1H), 7.55-7.50 (m, 2H), 7.07 (s, 1H), 6.09(s, 1H), 5.13 (q, J=6.5 Hz, 1H), 3.83-3.80 (m, 4H), 2.67 (brs, 1H),2.14-2.09 (m, 4H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.1239 g, 0.46mmol) and 3-acetylbenzeneboronic acid (0.0984 g, 0.60 mmol) were addedto a tube. The tube was evacuated and purged with argon (3×). 2 M Na₂CO₃(0.70 mL, 1.38 mmol) and DME (1.0 mL) were added and the solution wasdegassed for 15 minutes. Pd(PPh₃)₄ (0.0266 g, 0.023 mmol) was quicklyadded and the tube was heated at 100° C. overnight. Upon cooling to roomtemperature, the reaction was diluted with water and extracted withEtOAc. The combined organic layers were washed with H₂O (5×), saturatedNaHCO₃ (aq) and brine before drying with Na₂SO₄, filtering andconcentrating. The crude material was purified via flash chromatography(25% EtOAc/hexane) to afford 0.0391 g (28% yield) of TRV-1362 as orangesolid. ¹H NMR (CDCl₃, 500 MHz) δ=8.22 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.0Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.09 (s, 1H),6.10 (s, 1H), 3.82 (s, 4H), 2.68 (s, 3H), 2.13-2.11 (m, 4H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (1.00 g, 3.6 mmol) and isopropanol(0.31 mL, 4.0 mmol) were dissolved in THF (20 mL) under argon and cooledto −78° C. NaHMDS (4.0 mL of a 1.0 M solution in THF) was added dropwiseand the reaction was stirred for 30 minutes at −78° C. The cooling bathwas then removed and the reaction was stirred at room temperature for afew hours. The reaction was then cooled to 0° C. and quenched withsaturated NH₄Cl (aq) solution. This suspension was extracted with DCM(3×). The combined extracts were washed with H₂O, brine, dried (Na₂SO₄),filtered and concentrated to afford 0.9407 g of crude black oil. Thiscrude material (0.6702 g, 2.6 mmol) and 3-formylphenylboronic acid(0.5098 g, 3.4 mmol) were added to a tube. The tube was evacuated andpurged with argon (3×). 2 M Na₂CO₃ (3.9 mL, 7.8 mmol) and DME (5.8 mL)were added and the solution was degassed for 15 minutes. Pd(PPh₃)₄(0.1502 g, 0.13 mmol) was quickly added and the tube was heated at 100°C. overnight. Upon cooling to room temperature, the reaction was dilutedwith water and extracted with ethyl acetate. The combined organic layerswere washed with H₂O (5×), saturated NaHCO₃ (aq) and brine before dryingwith Na₂SO₄, filtering and concentrating. This crude material waspurified via flash chromatography (20% EtOAc/hexane) to afford 0.4836 g(66% yield) of the aldehyde. This aldehyde (0.6702 g, 2.6 mmol) wasdissolved in THF (2.0 mL) and cooled to 0° C. CF₃TMS (0.23 mL, 1.56mmol) was added followed by TBAF (0.1 mL, 0.1 mmol) at 0° C. After theaddition was complete, the ice bath was removed and the reaction wasstirred at room temperature for several hours. The mixture was thenre-cooled to 0° C. and TBAF (2.8 mL, 2.8 mmol) was added to thereaction, which was stirred overnight. The reaction was quenched withbrine and extracted with EtOAc. The combined extracts were washed withH₂O (4×), brine, dried (Na₂SO₄), filtered and concentrated. Purificationvia flash chromatography (25% EtOAc/hexane) afford 0.1468 g (53% yield,over 2 steps) of TRV-1363 as yellow oil. ¹H NMR (CDCl₃, 500 MHz) δ=7.74(s, 1H), 7.66 (dt, J=7.0, 2.0 Hz, 1H), 7.58-7.54 (m, 2H), 7.48 (s, 1H),6.78 (s, 1H), 5.17-5.13 (m, 1H), 4.99 (sept, J=6.0 Hz, 1H), 2.76 (d,J=4.5 Hz, 1H), 1.52 (d, J=6.0 Hz, 6H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.3898 g, 1.45mmol) and 5-formyl-2-thienylboronic acid (0.2948 g, 1.89 mmol) wereadded to a tube. The tube was evacuated and purged with argon 3 times.Then 2M Na₂CO₃ (aq) (2.2 mL) and DME (3.3 mL) were added and thesolution was degassed for 15 minutes. Pd(PPh₃)₄ (0.0844 g, 0.073 mmol)was added quickly, the tube was sealed and heated to 100° C. overnight.Upon cooling to room temperature, it was determined that the reactionwas not complete. Another equivalent of 5-formyl-2-thienylboronic acidwas added along with an additional 5 mol % of Pd(PPh₃)₄ and the mixturewas heated overnight again. It was necessary to added more boronic acidand catalyst once again, and heated for an additional 24 hours. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and then the aqueous layer wasback-extracted with EtOAc. The combined organic extracts were washedwith water (3×), brine, dried (Na₂SO₄), filtered and concentrated. Thecrude material was taken up in THF (3 mL) and CF₃TMS (0.43 mL, 2.9 mmol)was added. This solution was cooled to 0° C. before adding TBAF (0.15mL, 0.145 mmol). The mixture was stirred overnight and then anadditional 2 eq of CF₃TMS and 0.1 eq of TBAF were added. After stirringfor an additional 2 hours, the reaction was cooled to 0° C. and TBAF (8mL, 8 mmol) was added. The mixture was stirred overnight before dilutingwith water. The aqueous layer was extracted with EtOAc (3×). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The crude material was purified via column (15-20%EtOAc/hexane) to give 0.1043 g (19% yield, 3 steps) of TRV-1364 asorange solid. ¹H NMR (CDCl₃, 700 MHz) δ=7.35 (d, J=3.2 Hz, 1H), 7.19 (d,J=3.2 Hz, 1H), 7.13 (s, 1H), 6.10 (s, 1H), 5.31 (q, J=3.2 Hz, 1H), 3.80(br s, 4H), 2.90 (br s, 1H), 2.11 (s, 4H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.3948 g, 1.47mmol) and 4-formylbenzeneboronic acid (0.2864 g, 1.91 mmol) were addedto a tube. The tube was evacuated and purged with argon 3 times. Then 2MNa₂CO₃ (aq) (2.2 mL) and DME (3.3 mL) were added and the solution wasdegassed for 15 minutes. Pd(PPh₃)₄ (0.0855 g, 0.074 mmol) was addedquickly, the tube was sealed and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and then the aqueous layer wasback-extracted with EtOAc. The combined organic extracts were washedwith water (3×), brine, dried (Na₂SO₄), filtered and concentrated. Thecrude material was taken up in THF (3 mL) and CF₃TMS (0.43 mL, 2.94mmol) was added. This solution was cooled to 0° C. before adding TBAF(0.15 mL, 0.147 mmol). After stirring for 2 hours, the reaction wascooled to 0° C. and TBAF (5.1 mL, 5.1 mmol) was added. The mixture wasstirred overnight before diluting with water. The aqueous layer wasextracted with EtOAc (3×). The combined extracts were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified via column (15% EtOAc/hexane) to give 0.3795 g (71% yield, 3steps) of TRV-1365 as orange solid. ¹H NMR (CDCl₃, 700 MHz) δ=7.68 (d,J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.07 (s, 1H), 6.10 (s, 1H), 5.11(q, J=6.3 Hz, 1H), 3.81 (br s, 4H), 2.72 (br s, 1H), 2.13-2.09 (m, 4H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.3856 g, 1.44mmol) and 2-formylbenzeneboronic acid (0.2804 g, 1.87 mmol) were addedto a tube. The tube was evacuated and purged with argon 3 times. Then 2MNa₂CO₃ (aq) (2.2 mL) and DME (3.3 mL) were added and the solution wasdegassed for 15 minutes. Pd(PPh₃)₄ (0.0832 g, 0.072 mmol) was addedquickly, the tube was sealed and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and then the aqueous layer wasback-extracted with EtOAc. The combined organic extracts were washedwith water (3×), brine, dried (Na₂SO₄), filtered and concentrated. Thecrude material was taken up in THF (3 mL) and CF₃TMS (0.43 mL, 2.94mmol) was added. This solution was cooled to 0° C. before adding TBAF(0.14 mL, 0.144 mmol). After stirring for 2 hours, the reaction wascooled to 0° C. and TBAF (5.0 mL, 5.0 mmol) was added. The mixture wasstirred overnight before diluting with water. The aqueous layer wasextracted with EtOAc (3×). The combined extracts were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified via column (10% EtOAc/hexane) to give 0.179 g (34% yield, 3steps) of TRV-1366 as orange solid. ¹H NMR (CDCl₃, 500 MHz) δ=7.78 (d,J=8.0 Hz, 1H), 7.52-7.45 (m, 2H), 7.34 (d, J=7.5 Hz, 1H), 6.85 (s, 1H),5.79 (s, 1H), 5.26 (q, J=6.5 Hz, 1H), 3.76 (br s, 4H), 2.55 (br s, 1H),2.11-2.08 (m, 4H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.7754 g, 2.89mmol) was dissolved in THF and cooled to −78° C. nBuLi (1.6 mL of a 2.0M solution in cyclohexane) was added dropwise and the mixture wasallowed to stir for 30 minutes. At this point, to the solution which wasstirring at −78° C. was added DMF (0.25 mL, 3.18 mmol) all at once at−78° C. The reaction was stirred for 30 minutes and then allowed to warmto room temperature. The reaction was then quenched with saturatedNH₄Cl(aq), extracted with EtOAc. The combined organic layers were washedwith water, brine, dried (Na₂SO₄), filtered and concentrated to afford0.4779 g of crude aldehyde. This aldehyde (0.1352 g, 0.622 mmol) wasdissolved in THF (2 mL) and treated with CF₃TMS (0.18 mL, 1.24 mmol).The solution was cooled to 0° C. and then TBAF (0.1 mL, 0.1 mmol) wasadded. After stirring for 2 hours, the mixture was re-cooled to 0° C.and TBAF (2.2 mL, 2.2 mmol) was added, the reaction was allowed to stirovernight. The mixture was then quenched with water and extracted withEtOAc. The combined extracts were washed with water, brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified viacolumn (25% EtOAc/hexane) to afford 0.0201 g (11% yield) of TRV-1368 asred oil. ¹H NMR (CDCl₃, 700 MHz) δ=7.06 (s, 1H), 5.97 (s, 1H), 5.01 (q,J=6.3 Hz, 1H), 3.78 (br s, 4H), 2.74 (br s, 1H), 2.12-2.08 (m, 4H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.5785 g, 2.16mmol) and pyridine-3-boronic acid (0.3442 g, 2.8 mmol) were added to atube. The tube was evacuated and purged with argon 3 times. Then 2MNa₂CO₃ (aq) (3.2 mL) and DME (4.8 mL) were added and the solution wasdegassed for 15 minutes. Pd(PPh₃)₄ (0.1248 g, 0.108 mmol) was addedquickly, the tube was sealed and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and then the aqueous layer wasback-extracted with EtOAc. The combined organic extracts were washedwith water (3×), brine, dried (Na₂SO₄), filtered and concentrated. Thiscrude material was purified via column (50% EtOAc/hexane) to afford0.1902 g of contaminated material and 0.2624 g of pure material for acombined yield of 79% yield of TRV-1369 as orange solid. ¹H NMR (CDCl₃,700 MHz) δ=8.90 (d, J=1.4 Hz, 1H), 8.65 (d, J=4.6 Hz, 1H), 7.93 (d,J=7.7 Hz, 1H), 7.39 (dd, J=7.7, 4.6 Hz, 1H), 7.07 (s, 1H), 6.05 (s, 1H),3.82 (br s, 4H), 2.14-2.10 (m, 4H).

6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole 1 (0.7754 g, 2.89mmol) was dissolved in THF and cooled to −78° C. nBuLi (1.6 mL of a 2.0M solution in cyclohexane) was added dropwise and the mixture wasallowed to stir for 30 minutes. At this point, a 2.9 mL aliquot wastaken and added dropwise to an ice-cold solution of saturated NH₄Cl(aq). After warming to room temperature, the mixture was extracted withEtOAc. The combined extracts were washed with water, brine, dried(Na₂SO₄), filtered and concentrated. This crude material was purifiedvia column (5% EtOAc/hexane) to afford 0.0654 g (46% yield) of TRV-1370as orange solid. ¹H NMR (CDCl₃, 500 MHz) δ=7.22 (dd, J=8.5, 8.0 Hz, 1H),6.91 (d, J=8.5 Hz, 1H), 5.87 (d, J=8.0 Hz, 1H), 3.76-3.73 (m, 4H),2.10-2.05 (m, 4H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (1.0173 g, 3.66 mmol),4-methylimidazole (0.3005 g, 3.66 mmol), NMP (5 mL) and DIPEA (0.64 mL,3.66 mmol) was sealed in a tube and heated to 150° C. for 3 days. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O,1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude material was purified via35% EtOAc/Hexane column to afford 0.5295 g (52% yield) of the aniline.The aniline (0.2988 g, 1.07 mmol) and 3-formylbenzeneboronic acid(0.2084 g, 1.39 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.6 mL, aq solution) was addedalong with DME (2.4 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.0618 g, 0.0535 mmol) was added all at once. The tubewas re-sealed and heated to 100° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. This crude material was thendissolved in THF (2 mL) and cooled in an ice bath. To this solution wasadded CF₃TMS (0.24 mL, 1.61 mmol) and then TBAF (0.1 mL, 1.0 M solutionin THF). After 5 minutes, the ice bath was removed and the mixture wasstirred for an additional 2 hours. The solution was then re-cooled to 0°C. and TBAF (3.2 mL, 3.2 mmol) was added, the mixture was allowed towarm to room temperature overnight. The mixture was diluted with waterand EtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O(3×), brine and then dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified via chromatography (5% MeOH/DCM) to afford0.0616 g (15% yield, 3 steps) of TRV-1375 as a 1:1 mixture ofregioisomers. ¹H NMR (500 MHz, CDCl3) δ=8.353 (s, 1H), 8.350 (s, 1H),7.89 (s, 1H), 7.88 (s, 1H), 7.85 (s, 2H), 7.71-7.69 (m, 2H), 7.65-7.63(m, 2H), 7.61-7.56 (m, 4H), 7.48 (s, 2H), 5.20 (q, J=7.0 Hz, 2H), 5.07(br s, 2H), 2.332 (s, 3H), 2.331 (s, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3327 g, 1.2 mmol),1-methylpiperazine (0.13 mL, 1.2 mmol), NMP (2 mL) and DIPEA (0.21 mL,1.2 mmol) was sealed in a tube and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O,1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2338 g, 1.56 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.8mL, aq solution) was added along with DME (2.7 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0693 g, 0.06 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.35 mL, 2.4 mmol) and thenTBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bath wasremoved and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.2 mL, 4.2 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (5% MeOH/DCM) to afford 0.1695 g (36% yield, 4 steps) ofTRV-1376. ¹H NMR (500 MHz, DMSO) δ=7.91 (s, 1H), 7.85-7.83 (m, 1H),7.60-7.54 (m, 2H), 7.54 (s, 1H), 6.94 (d, J=6.0 Hz, 1H), 6.75 (s, 1H),5.31-5.28 (m, 1H), 3.64 (t, J=5.0 Hz, 4H), 2.55 (t, J=5.0 Hz, 4H), 2.25(s, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3113 g, 1.12 mmol),N-isopropylmethylamine (0.12 mL, 1.12 mmol), NMP (2 mL) and DIPEA (0.20mL, 1.12 mmol) was sealed in a tube and heated to 100° C. overnight.Upon cooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O,1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2189 g, 1.46 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.7mL, aq solution) was added along with DME (2.5 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0647 g, 0.056 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.33 mL, 2.24 mmol) andthen TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.0 mL, 4.0 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (15% EtOAc/hexane) to afford 0.1283 g (31% yield, 4steps) of TRV-1377. ¹H NMR (500 MHz, CDCl3) δ=7.74 (s, 1H), 7.68 (dt,J=5.0, 2.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.18 (d, J=1.0 Hz, 1H), 6.30 (s,1H), 5.24 (sept, J=6.5 Hz, 1H), 5.13 (q, J=6.5 Hz, 1H), 3.01 (s, 3H),2.71 (br s, 1H), 1.30 (d, J=6.5 Hz, 6H).

N-benzyl-6-bromo-N-methylbenzo[c][1,2,5]oxadiazol-4-amine and3-formylbenzeneboronic acid (0.2293 g, 1.53 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.8mL, aq solution) was added along with DME (2.6 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0682 g, 0.059 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.35 mL, 2.36 mmol) andthen TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.2 mL, 4.2 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (15% EtOAc/hexane) to afford 0.2683 g (55% yield, 4steps) of TRV-1378. ¹H NMR (500 MHz, CDCl3) δ=7.69 (s, 1H), 7.64 (dt,J=7.5, 1.5 Hz, 1H), 7.54-7.49 (m, 2H), 7.35-7.32 (m, 2H), 7.29-7.26 (m,3H), 7.23 (d, J=1.0 Hz, 1H), 6.33 (s, 1H), 5.16 (s, 2H), 5.11 (q, J=6.5Hz, 1H), 3.24 (s, 3H), 2.68 (s, 1H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3414 g, 1.23 mmol),2-methylpyrrolidine (0.13 mL, 1.23 mmol), NMP (2 mL) and DIPEA (0.21 mL,1.23 mmol) was sealed in a tube and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O,1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2398 g, 1.6 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.9mL, aq solution) was added along with DME (2.8 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0716 g, 0.062 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.36 mL, 2.46 mmol) andthen TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.3 mL, 4.3 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (15% EtOAc/hexane) to afford 0.1319 g (28% yield, 4steps) of TRV-1379, a 1:1:1:1 mixture of diastereomers due to the twochiral centers. ¹H NMR (500 MHz, CDCl3) δ=7.74 (s, 1H), 7.67 (dt, J=7.0,2.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.07 (s, 1H), 6.12 (s, 1H), 5.13 (q,J=6.5 Hz, 1H), 4.75-4.71 (m, 1H), 3.87-3.83 (m, 1H), 3.65-3.60 (m, 1H),2.71 (br s, 1H), 2.24-2.08 (m, 3H), 1.85-1.81 (m, 1H), 1.29 (d, J=6.5Hz, 3H).

N-benzyl-6-bromobenzo[c][1,2,5]oxadiazol-4-amine and3-formylbenzeneboronic acid (0.2488 g, 1.66 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.9mL, aq solution) was added along with DME (2.9 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.074 g, 0.064 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (3 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.28 mL, 1.92 mmol) andthen TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (3.9 mL, 3.9 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (15% EtOAc/hexane) to afford 0.0655 g (13% yield, 4steps) of TRV-1380. ¹H NMR (500 MHz, CDCl3) δ=7.67 (s, 1H), 7.63 (dt,J=7.5, 1.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.49-7.42 (m, 4H), 7.40-7.36 (m,1H), 7.22 (d, J=1.0 Hz, 1H), 6.37 (s, 1H), 5.51 (t, J=5.0 Hz, 1H), 5.14(q, J=6.5 Hz, 1H), 4.60 (d, J=5.0 Hz, 2H), 2.72 (br s, 1H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3095 g, 1.11 mmol), piperidine(0.11 mL, 1.11 mmol), NMP (2 mL) and DIPEA (0.19 mL, 1.11 mmol) weresealed in a tube and heated to 100° C. overnight. Upon cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O, 1 N HCl (aq),saturated NaHCO₃ (aq), H₂O (3×), brine and then dried (Na₂SO₄), filteredand concentrated. The crude aniline and 3-formylbenzeneboronic acid(0.2159 g, 1.44 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.7 mL, aq solution) was addedalong with DME (2.5 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.0647 g, 0.056 mmol) was added all at once. The tubewas re-sealed and heated to 100° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. This crude material was thendissolved in THF (2.5 mL) and cooled in an ice bath. To this solutionwas added CF₃TMS (0.33 mL, 2.22 mmol) and then TBAF (0.1 mL, 1.0 Msolution in THF). After 5 minutes, the ice bath was removed and themixture was stirred for an additional 2 hours. The solution was thenre-cooled to 0° C. and TBAF (3.9 mL, 3.9 mmol) was added, the mixturewas allowed to warm to room temperature overnight. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was then back-extracted. The combined organic extracts were thenwashed with H₂O (3×), brine and then dried (Na₂SO₄), filtered andconcentrated. The crude material was purified via chromatography (20%EtOAc/hexane) to afford 0.3097 g (74% yield, 4 steps) of TRV-1381. ¹HNMR (500 MHz, CDCl3) δ=7.73 (s, 1H), 7.67-7.66 (m, 1H), 7.57-7.51 (m,2H), 7.30 (s, 1H), 6.53 (s, 1H), 5.14 (q, J=6.5 Hz, 1H), 3.65 (t, J=5.5Hz, 4H), 2.70 (br s, 1H), 1.84-1.77 (m, 4H), 1.74-1.69 (m, 2H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3340 g, 1.2 mmol), diethylamine(0.13 mL, 1.2 mmol), NMP (2 mL) and DIPEA (0.21 mL, 1.2 mmol) weresealed in a tube and heated to 100° C. overnight. Upon cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O, 1 N HCl (aq),saturated NaHCO₃ (aq), H₂O (3×), brine and then dried (Na₂SO₄), filteredand concentrated. The crude aniline and 3-formylbenzeneboronic acid(0.2338 g, 1.56 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.8 mL, aq solution) was addedalong with DME (2.7 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.0693 g, 0.06 mmol) was added all at once. The tube wasre-sealed and heated to 100° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. This crude material was thendissolved in THF (2.5 mL) and cooled in an ice bath. To this solutionwas added CF₃TMS (0.35 mL, 2.4 mmol) and then TBAF (0.1 mL, 1.0 Msolution in THF). After 5 minutes, the ice bath was removed and themixture was stirred for an additional 2 hours. The solution was thenre-cooled to 0° C. and TBAF (4.2 mL, 4.2 mmol) was added, the mixturewas allowed to warm to room temperature overnight. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was then back-extracted. The combined organic extracts were thenwashed with H₂O (3×), brine and then dried (Na₂SO₄), filtered andconcentrated. The crude material was purified via chromatography (20%EtOAc/hexane) to afford 0.2184 g (50% yield, 4 steps) of TRV-1382. ¹HNMR (500 MHz, CDCl3) δ=7.73 (s, 1H), 7.65 (dt, J=7.0, 2.0 Hz, 1H),7.55-7.51 (m, 2H), 7.11 (d, J=0.5 Hz, 1H), 6.25 (s, 1H), 5.13 (q, J=6.5Hz, 1H), 3.81 (q, J=7.0 Hz, 4H), 2.76 (br s, 1H), 1.31 (t, J=7.0 Hz,6H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3322 g, 1.2 mmol),(2-methoxyethyl)methylamine (0.13 mL, 1.2 mmol), NMP (2 mL) and DIPEA(0.21 mL, 1.2 mmol) were sealed in a tube and heated to 100° C.overnight. Upon cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O, 1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2338 g, 1.56 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.8mL, aq solution) was added along with DME (2.7 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0693 g, 0.06 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.35 mL, 2.4 mmol) and thenTBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bath wasremoved and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.2 mL, 4.2 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (20% EtOAc/hexane) to afford 0.2514 g (55% yield, 4steps) of TRV-1383. ¹H NMR (500 MHz, CDCl3) δ=7.75 (s, 1H), 7.68 (dt,J=7.0, 2.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.17 (d, J=1.0 Hz, 1H), 6.28 (s,1H), 5.13 (q, J=7.0 Hz, 1H), 4.18 (t, J=5.5 Hz, 2H), 3.68 (t, J=5.5 Hz,2H), 3.35 (s, 3H), 3.28 (s, 3H), 2.78 (br s, 1H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3327 g, 1.2 mmol),N-methylethanamie (0.10 mL, 1.2 mmol), NMP (2 mL) and DIPEA (0.21 mL,1.2 mmol) were sealed in a tube and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O,1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2338 g, 1.56 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.8mL, aq solution) was added along with DME (2.7 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0693 g, 0.06 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.35 mL, 2.4 mmol) and thenTBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bath wasremoved and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.2 mL, 4.2 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (20% EtOAc/hexane) to afford 0.2528 g (60% yield, 4steps) of TRV-1384. ¹H NMR (500 MHz, CDCl3) δ=7.74 (s, 1H), 7.66 (dt,J=7.0, 2.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.15 (d, J=1.0 Hz, 1H), 6.23 (s,1H), 5.13 (q, J=7.0 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.22 (s, 3H), 2.78(br s, 1H), 1.25 (t, J=7.0 Hz, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3373 g, 1.2 mmol),thiomorpholine (0.12 mL, 1.2 mmol), NMP (2 mL) and DIPEA (0.21 mL, 1.2mmol) were sealed in a tube and heated to 100° C. overnight. Uponcooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O,1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2338 g, 1.56 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.8mL, aq solution) was added along with DME (2.7 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0693 g, 0.06 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.35 mL, 2.4 mmol) and thenTBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bath wasremoved and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.2 mL, 4.2 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (20% EtOAc/hexane) to afford 0.1863 g (39% yield, 4steps) of TRV-1385. ¹H NMR (500 MHz, CDCl3) δ=7.73 (s, 1H), 7.65 (dt,J=7.0, 2.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.34 (d, J=0.5 Hz, 1H), 6.55 (s,1H), 5.14 (q, J=6.5 Hz, 1H), 4.06 (m, 4H), 2.86 (m, 4H), 2.76 (br s,1H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (8.9 g, 32.0 mmol) and3-formylbenzeneboronic acid (5.037 g, 33.6 mmol) were charged to aflask. The flask was evacuated and purged with argon (3 cycles). 2MNa₂CO₃ (48 mL, aq solution) was added along with DME (72 mL). Thesolution was degassed for 15 minutes and then Pd(PPh₃)₄ (1.85 g, 1.6mmol) was added all at once. The flask was heated to 100° C. for 4hours. After cooling to room temperature, the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasthen back-extracted. The combined organic extracts were then washed withH₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated togive 13.3 g of a yellow solid that was a mixture of the desired product,unreacted starting material, the wrong regioisomer and the his-coupledproduct. Purification of the crude material via chromatography (0, 5,10, 15, 20% EtOAc/hexane gradient elution) afforded 1.9412 g (20% yield)of 3-(7-bromobenzo[c][1,2,5]oxadiazol-5-yl)benzaldehyde. This material(1.7903 g, 5.91 mmol) was then dissolved in THF (12 mL) and cooled in anice bath. To this solution was added CF₃TMS (1.75 mL, 11.8 mmol) andthen TBAF (0.6 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (22 mL, 22 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. This crude material was dissolved in THF (15mL) and cooled to 0° C. NaH (0.2836 g, 7.09 mmol) was added portion wiseand the reaction was stirred for 10 minutes at 0° C. before warming toroom temperature and stirring an additional 30 minutes. The solution wasthen re-cooled and TBSCl (1.336 g, 8.87 mmol) was added. The reactionwas stirred overnight under argon. Cooled to 0° C. and quenched withsaturated NH₄Cl (aq) and then diluted with EtOAc. The layers wereseparated and the aqueous layer was then back-extracted. The combinedorganic extracts were then washed with H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude material was purified bychromatography (5% EtOAc/hexane) to afford 1.2744 g (44% yield, 3 steps)of the corresponding silyl ether as a brown solid. This material (0.2732g, 0.56 mmol) was dissolved in THF (5 mL) and cooled to −78° C. nBuLi(0.31 mL, 2.0 M solution in cyclohexane, 0.62 mmol) was added dropwiseand the solution was stirred for 30 minutes before quenching withsaturated NH₄Cl (aq) and allowed to warm to room temperature. Themixture was diluted with water and EtOAc. The layers were separated andthe aqueous layer was then back-extracted. The combined organic extractswere then washed with H₂O (3×), brine and then dried (Na₂SO₄), filteredand concentrated. This crude material was dissolved in THF (10 mL) andcooled to 0° C. TBAF (1.2 mL, 1.0 M solution in THF) was added and thereaction was allowed to warm to room temperature overnight. The reactionwas quenched with brine. The mixture was then diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O(3×), brine and then dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified via chromatography

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3832 g, 1.38 mmol),4-(pyrrolidin-1-yl)piperidine (0.2127 g, 1.38 mmol), NMP (2 mL) andDIPEA (0.24 mL, 1.38 mmol) were sealed in a tube and heated to 100° C.overnight. Upon cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.The crude aniline and 3-formylbenzeneboronic acid (0.2698 g, 1.8 mmol)were sealed in a tube. The tube was evacuated and purged with argon (3cycles). 2M Na₂CO₃ (2.1 mL, aq solution) was added along with DME (3.1mL). The solution was degassed for 10 minutes and then Pd(PPh₃)₄ (0.0797g, 0.069 mmol) was added all at once. The tube was re-sealed and heatedto 100° C. overnight. After cooling to room temperature, the mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was then back-extracted. The combined organic extracts were thenwashed with H₂O (3×), brine and then dried (Na₂SO₄), filtered andconcentrated. This crude material was then dissolved in THF (2.8 mL) andcooled in an ice bath. To this solution was added CF₃TMS (0.41 mL, 2.76mmol) and then TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes,the ice bath was removed and the mixture was stirred for an additional 2hours. The solution was then re-cooled to 0° C. and TBAF (4.8 mL, 4.8mmol) was added, the mixture was allowed to warm to room temperatureovernight. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was then back-extracted. The combinedorganic extracts were then washed with H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude material was purified viachromatography (10% MeOH/DCM) to afford 0.1349 g (22% yield, 4 steps) ofTRV-1387. ¹H NMR (500 MHz, CDCl3) δ=7.73 (s, 1H), 7.59 (d, J=7.5 Hz,1H), 7.53-7.46 (m, 2H), 7.25 (s, 1H), 6.48 (s, 1H), 5.08 (q, J=6.5 Hz,1H), 4.34-4.28 (m, 2H), 3.05-3.00 (m, 2H), 2.65 (br s, 4H), 2.30-2.27(m, 1H), 2.06-2.03 (m, 2H), 1.84 (br s, 4H), 1.77-1.66 (m, 3H); ¹H NMR(DMSO, 500 MHz) δ=7.91 (s, 1H), 7.83 (d, J=10 Hz, 1H), 7.59 (d, J=10 Hz,1H), 7.55 (t, J=10 Hz, 1H), 7.50 (s, 1H), 6.97 (d, J=5 Hz, 1H), 6.73 (s,1H), 5.31-5.26 (m, 1H), 4.20 (d, J=10 Hz, 2H), 3.16 (t, J=10 Hz, 2H),2.52 (s, 4H), 2.26-2.22 (m, 1H), 2.00 (d, J=10 Hz, 2H), 1.67 (s, 4H),1.63-1.56 (m, 2H).

To a solution of 4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3106 g, 1.12mmol) and pyrazole (0.0837 g, 1.23 mmol) in THF at −78° C. was addedNaHMDS (1.2 mL, 1.0 M solution in THF) dropwise. The solution wasstirred for 30 minutes then warmed to room temperature. The solution wasthen degassed for 5 minutes before heating to 50° C. overnight. Uponcooling to room temperature, the reaction was quenched with saturatedNH₄Cl (aq) and diluted with EtOAc. The layers were separated and theaqueous layer was then back-extracted. The combined organic extractswere then washed with H₂O (3×), brine and then dried (Na₂SO₄), filteredand concentrated. The crude aniline and 3-formylbenzeneboronic acid(0.2189 g, 1.46 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.7 mL, aq solution) was addedalong with DME (2.5 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.0647 g, 0.056 mmol) was added all at once. The tubewas re-sealed and heated to 100° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. This crude material was thendissolved in THF (2.5 mL) and cooled in an ice bath. To this solutionwas added CF₃TMS (0.33 mL, 2.24 mmol) and then TBAF (0.1 mL, 1.0 Msolution in THF). After 5 minutes, the ice bath was removed and themixture was stirred for an additional 2 hours. The solution was thenre-cooled to 0° C. and TBAF (3.9 mL, 3.9 mmol) was added, the mixturewas allowed to warm to room temperature overnight. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was then back-extracted. The combined organic extracts were thenwashed with H₂O (3×), brine and then dried (Na₂SO₄), filtered andconcentrated. The crude material was purified via chromatography (20%EtOAc/hexane) to afford 0.0342 g (8.5% yield, 4 steps) of TRV-1388. ¹HNMR (500 MHz, CDCl3) δ=8.91 (d, J=2.5 Hz, 1H), 8.33 (d, J=1.5 Hz, 1H),7.84-7.83 (m, 3H), 7.76 (dt, J=7.5, 1.5 Hz, 1H), 7.59-7.52 (m, 2H),6.62-6.61 (m, 1H), 5.15-5.12 (m, 1H), 3.40 (d, J=4.0 Hz, 1H).

To a solution of 4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3457 g, 1.24mmol) and 4-methylpyrazole (0.11 mL, 1.37 mmol) in THF at −78° C. wasadded NaHMDS (1.3 mL, 1.0 M solution in THF) dropwise. The solution wasstirred for 30 minutes then warmed to room temperature. The solution wasthen degassed for 5 minutes before heating to 50° C. overnight. Uponcooling to room temperature, the reaction was quenched with saturatedNH₄Cl (aq) and diluted with EtOAc. The layers were separated and theaqueous layer was then back-extracted.

The combined organic extracts were then washed with H₂O (3×), brine andthen dried (Na₂SO₄), filtered and concentrated. The crude aniline and3-formylbenzeneboronic acid (0.2413 g, 1.61 mmol) were sealed in a tube.The tube was evacuated and purged with argon (3 cycles). 2M Na₂CO₃ (1.9mL, aq solution) was added along with DME (2.8 mL). The solution wasdegassed for 10 minutes and then Pd(PPh₃)₄ (0.0716 g, 0.062 mmol) wasadded all at once. The tube was re-sealed and heated to 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated.This crude material was then dissolved in THF (2.5 mL) and cooled in anice bath. To this solution was added CF₃TMS (0.37 mL, 2.48 mmol) andthen TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (4.3 mL, 4.3 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (20% EtOAc/hexane) to afford 0.0365 g (7.9% yield, 4steps) of TRV-1389. ¹H NMR (500 MHz, CDCl3) δ=8.68 (s, 1H), 8.28 (d,J=1.0 Hz, 1H), 7.84 (s, 1H), 7.81 (d, J=1.0 Hz, 1H), 7.76 (d, J=7.5 Hz,1H), 7.66 (s, 1H), 7.60-7.54 (m, 2H), 5.16-5.14 (m, 1H), 3.06 (d, J=3.5Hz, 1H), 2.23 (s, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3688 g, 1.33 mmol),4-fluoro-N-methylbenzylamine (0.18 mL, 1.39 mmol), NMP (3 mL) and DIPEA(0.26 mL, 1.5 mmol) were sealed in a tube and heated to 100° C.overnight. Upon cooling to room temperature, the mixture was dilutedwith water and EtOAc. The layers were separated and the aqueous layerwas then back-extracted. The combined organic extracts were then washedwith H₂O, 1 N HCl (aq), saturated NaHCO₃ (aq), H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated to give6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine. Thecrude aniline and 3-formylbenzeneboronic acid (0.2593 g, 1.73 mmol) weresealed in a tube. The tube was evacuated and purged with argon (3cycles). 2M Na₂CO₃ (2.0 mL, aq solution) was added along with DME (3.0mL). The solution was degassed for 10 minutes and then Pd(PPh₃)₄ (0.0768g, 0.066 mmol) was added all at once. The tube was re-sealed and heatedto 100° C. overnight. After cooling to room temperature, the mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was then back-extracted. The combined organic extracts were thenwashed with H₂O (3×), brine and then dried (Na₂SO₄), filtered andconcentrated. This crude material was then dissolved in THF (4.0 mL) andcooled in an ice bath. To this solution was added CF₃TMS (0.39 mL, 2.66mmol) and then TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes,the ice bath was removed and the mixture was stirred for an additional 2hours. The solution was then re-cooled to 0° C. and TBAF (4.7 mL, 4.7mmol) was added, the mixture was allowed to warm to room temperatureovernight. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was then back-extracted. The combinedorganic extracts were then washed with H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude material was purified viachromatography (15% EtOAc/hexane) to afford 0.2675 g (47% yield, 4steps) of TRV-1390. ¹H NMR (500 MHz, CDCl3) δ=7.70 (s, 1H), 7.64 (dt,J=7.0, 2.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.27-7.24 (m, 3H), 7.04-7.00 (m,2H), 6.34 (s, 1H), 5.12-5.10 (m, 3H), 3.19 (s, 3H), 2.71 (s, 1H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (8.9 g, 32.0 mmol) and3-formylbenzeneboronic acid (5.037 g, 33.6 mmol) were charged to aflask. The flask was evacuated and purged with argon (3 cycles). 2MNa₂CO₃ (48 mL, aq solution) was added along with DME (72 mL). Thesolution was degassed for 15 minutes and then Pd(PPh₃)₄ (1.85 g, 1.6mmol) was added all at once. The flask was heated to 100° C. for 4hours. After cooling to room temperature, the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasthen back-extracted. The combined organic extracts were then washed withH₂O (3×), brine and then dried (Na₂SO₄), filtered and concentrated togive 13.3 g of a yellow solid that was a mixture of the desired product,unreacted starting material, the wrong regioisomer, and the his-coupledproduct. Purification of the crude material via chromatography (0, 5,10, 15, 20% EtOAc/hexane gradient elution) afforded 1.9412 g (20% yield)of 3-(7-bromobenzo[c][1,2,5]oxadiazol-5-yl)benzaldehyde. This material(1.7903 g, 5.91 mmol) was then dissolved in THF (12 mL) and cooled in anice bath. To this solution was added CF₃TMS (1.75 mL, 11.8 mmol) andthen TBAF (0.6 mL, 1.0 M solution in THF). After 5 minutes, the ice bathwas removed and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (22 mL, 22 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined organicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. This crude material was dissolved in THF (15mL) and cooled to 0° C. NaH (0.2836 g, 7.09 mmol) was added portion wiseand the reaction was stirred for 10 minutes at 0° C. before warming toroom temperature and stirring an additional 30 minutes. The solution wasthen re-cooled and TBSCl (1.336 g, 8.87 mmol) was added. The reactionwas stirred overnight under argon. Cooled to 0° C. and quenched withsaturated NH₄Cl (aq) and then diluted with EtOAc. The layers wereseparated and the aqueous layer was then back-extracted. The combinedorganic extracts were then washed with H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. The crude material was purified bychromatography (5% EtOAc/hexane) to afford 1.2744 g (44% yield, 3 steps)of brown solid. This solid (0.2647 g, 0.543 mmol) was dissolved in THF(5 mL) and cooled to −78° C. nBuLi (0.30 mL, 2.0 M solution incyclohexane, 0.60 mmol) was added dropwise and the solution was stirredfor 30 minutes before adding DMF (0.050 mL, 0.652 mmol). The mixture wasslowly allowed to warm to room temperature. The solution was thenre-cooled to 0° C. and quenched with saturated NH₄Cl (aq). This mixturewas extracted with EtOAc. The combined extracts were washed with water,brine, dried (Na₂SO₄), filtered and concentrated to give the crudealdehyde. The aldehyde was purified via flash chromatography (10%EtOAc/hexane) to give 0.0913 g (39% yield). This aldehyde was thendissolved in DCM (1 mL) and pyrrolidine (0.026 mL, 0.313 mmol) wasadded. To this mixture was then added NaHB(OAc)₃ (0.0886 g, 0.418 mmol)with vigorous stirring and the reaction was stirred overnight. Thereaction was quenched with saturated NaHCO₃ (aq) and extracted with DCM.The combined extracts were washed with water, brine and then dried(Na₂SO₄), filtered and concentrated. This material was then redissolvedin THF (2 mL) and cooled to 0° C. TBAF (0.42 mL, 1.0 M solution in THF)was added and the mixture was stirred overnight under argon. Thereaction was quenched with brine and extracted with EtOAc. The combinedextracts were washed with water, brine, dried (Na₂SO₄) filtered andconcentrated. The crude material was purified via flash chromatography(5% MeOH/DCM) to afford 0.0181 g (23% yield) of TRV-1391. ¹H NMR (CDCl3,500 MHz) δ=7.84 (t, J=0.5 Hz, 1H), 7.78 (s, 1H), 7.72-7.70 (m, 2H),7.58-7.54 (m, 2H), 5.15 (q, J=7.0 Hz, 1H), 4.12 (s, 2H), 2.69 (s, 4H),1.86-1.84 (m, 4H).

N-benzyl-6-bromo-N-methylbenzo[c][1,2,5]oxadiazol-4-amine (0.3720 g,1.17 mmol) was dissolved in THF (6 mL) under argon, and cooled to −78°C. nBuLi (0.65 mL, 2.0 M solution in cyclohexane) was added dropwiseforming a deep red solution. This mixture was stirred for 30 minutes at−78° C. and then DMF (0.11 mL, 1.4 mmol) was added quickly. The mixturewas allowed to slowly warm to room temperature. It was then re-cooled to0° C. and quenched with saturated NH₄Cl (aq). This mixture was extractedwith EtOAc. The combined extracts were washed with water, brine, dried(Na₂SO₄), filtered and concentrated to give the crude aldehyde. Thealdehyde was purified via flash chromatography (10% EtOAc/hexane) togive 0.1737 g (56% yield) of the aldehyde 4. This material (0.1737 g,0.546 mmol) was then dissolved in THF (2.0 mL) and cooled in an icebath. To this solution was added CF₃TMS (0.16 mL, 1.09 mmol) and thenTBAF (0.06 mL, 1.0 M solution in THF). After 5 minutes, the ice bath wasremoved and the mixture was stirred for an additional 2 hours. Thesolution was then re-cooled to 0° C. and TBAF (2.0 mL, 2.0 mmol) wasadded, the mixture was allowed to warm to room temperature overnight.The mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was then back-extracted. The combined dorganicextracts were then washed with H₂O (3×), brine and then dried (Na₂SO₄),filtered and concentrated. The crude material was purified viachromatography (15% EtOAc/hexane) to afford 0.1094 g (60% yield) ofTRV-1392. ¹H NMR (500 MHz, CDCl3) δ=7.38-7.35 (m, 2H), 7.33-7.28 (m,4H), 6.26 (s, 1H), 5.17 (s, 2H), 5.05 (q, J=6.5 Hz, 1H), 3.23 (s, 3H),2.79 (br s, 1H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.3753 g, 1.12 mmol) was dissolved in THF (6 mL) and cooled to −78° C.nBuLi (0.62 mL, 2.0 M solution in cyclohexane, 1.23 mmol) was addeddropwise and the solution was stirred for 30 minutes before adding DMF(0.10 mL, 1.34 mmol). The mixture was stirred under argon at −78° C.After 3 hours, saturated NH₄Cl (aq) was added and then the mixture wasallowed to warm to room temperature. This mixture was extracted withEtOAc. The combined extracts were washed with water, brine, dried(Na₂SO₄), filtered and concentrated to give the crude aldehyde. Thealdehyde was purified via flash chromatography (10% EtOAc/hexane) togive 0.1846 g (58% yield). This material (0.1846 g, 0.647 mmol) was thendissolved in THF (3 mL) and cooled in an ice bath. To this solution wasadded CF₃TMS (0.19 mL, 1.3 mmol) and then TBAF (0.06 mL, 1.0 M solutionin THF). After 5 minutes, the ice bath was removed and the mixture wasstirred for an additional 2 hours. The solution was then re-cooled to 0°C. and TBAF (2.3 mL, 2.26 mmol) was added, the mixture was allowed towarm to room temperature overnight. The mixture was diluted with waterand EtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combined organic extracts were then washed with H₂O(3×), brine and then dried (Na₂SO₄), filtered and concentrated. Thismaterial was purified via chromatography (20% EtOAc/hexane) to give0.0794 g (34% yield) TRV-1397 as a red oil. ¹H NMR (500 MHz, CDCl3)δ=7.26 (s, 1H), 7.24-7.22 (m, 2H), 7.03-6.99 (m, 2H), 6.23 (s, 1H), 5.09(s, 2H), 5.02 (q, J=7.0 Hz, 1H), 3.15 (s, 3H), 2.67 (br s, 1H).

TRV-1378 (83 mg, 0.2 mmol) was dissolved in THF (2 mL) and addeddropwise to a suspension of NaH (50 mg) stirring in THF (1 mL) at 0° C.Once the addition was complete the cold bath was removed and replacedwith a room temperature water bath. After 5 min the reaction was cooledback to 0° C. and MeI (100 μL, 0.8 mmol) was added. The cold bath wasleft in place and the reaction was allowed to come to room temperatureovernight. Following a standard workup and flash chromatography (9:1Hex/EtOAc). the product was isolated as an orange solid (54 mg, 63%yield). ¹H NMR (500 MHz, CDCl₃) δ=7.68 (m, 2H), 7.54 (m, 2H), 7.37 (m,2H), 7.32 (m, 4H), 6.38 (s, 1H), 5.20 (s, 2H0, 4.61 (q, J=7 Hz, 1H),3.52 (s, 3H), 3.29 (s, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.9837 g, 3.53 mmol), ethylamine(0.29 mL, 3.53 mmol), NMP (5 mL) and DIPEA (0.61 mL, 3.53 mmol) weresealed in a tube and heated to 60° C. overnight. Upon cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombined organic extracts were then washed with H₂O, 1 N HCl (aq),saturated NaHCO₃ (aq), H₂O (3×), brine and then dried (Na₂SO₄), filteredand concentrated. The crude material was purified via chromatography (3%EtOAc/hexane) to afford 0.3952 g (46% yield). This material (0.1298 g,0.54 mmol) was dissolved in Ac₂O (5 mL) and heated to 140° C. for 48hours. After cooling to room temperature the material was concentratedto afford 4 in 98% yield. This material (0.1499 g, 0.52 mmol) was addedto a tube along with 3-formylbenzenboronic acid (0.1013 g, 0.676 mmol)and the tube was purged and evacuated with argon (3 times). Na₂CO₃ (1.6mL, 3.12 mmol, 2 M aqueous solution) and DME (2.3 mL) were added and thesolution was degassed for 10 minutes. Finally Pd(PPh₃)₄ (0.030 g, 0.026mmol) was added, the tube was sealed and heated to 100° C. overnight.Upon cooling to room temperature, the mixture was diluted with EtOAc andwater. The layers were separated and the aqueous layer wasback-extracted with EtOAc (3×). The combined organic layers were washedwith H₂O (4×), brine, dried (Na₂SO₄), filtered and concentrated to givea crude aldehyde 6. This aldehyde was then dissolved in THF (3 mL) andcooled in an ice bath. To this solution was added CF₃TMS (0.08 mL, 0.52mmol) and then TBAF (0.05 mL, 1.0 M solution in THF). After 5 minutes,the ice bath was removed and the mixture was stirred for an additional 2hours. The solution was then re-cooled to 0° C. and TBAF (1.3 mL, 1.3mmol) was added, the mixture was allowed to warm to room temperatureovernight. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was then back-extracted. The combinedorganic extracts were then washed with H₂O (3×), brine and then dried(Na₂SO₄), filtered and concentrated. This material was purified viachromatography (40% EtOAc/hexane) to give 0.0327 g (17% yield over 3steps) of TRV-1399 as yellow solid. ¹H NMR (500 MHz, CDCl3) δ=7.98 (s,1H), 7.78 (s, 1H), 7.68-7.67 (m, 1H), 7.61-7.57 (m, 2H), 7.52 (s, 1H),5.19-5.14 (m, 1H), 3.97 (q, J=10 Hz, 2H), 3.33 (d, J=5 Hz, 1H), 2.02 (brs, 3H), 1.21 (t, J=10 Hz, 3H).

CsF (0.0052 g, 0.034 mmol) was added to a mixture of TRV-1402 (0.1162 g,0.34 mmol) and CF₃TMS (0.10 mL, 0.68 mmol) in THF (3 mL) at roomtemperature. This solution was stirred until 100% conversion of startingmaterial m was obtained and then TBAF (1.2 mL, 1.0 M solution in THF)was added, this was stirred for an additional 16 hours. The reaction wasquenched with brine and diluted with EtOAc and water. The layers wereseparated and the aqueous layer was back-extracted with EtOAc. Thecombined organic layers were washed with H₂O (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified via10% EtOAc/hexane column and then again with a 5% EtOAc/hexane column toafford 0.020 g (13% yield) of TRV-1400 as orange solid. ¹H NMR (500 MHz,CDCl3) δ=7.24-7.21 (m, 2H), 7.17 (d, J=15 Hz, 1H), 7.16 (s, 1H),7.03-6.99 (m, 2H), 6.23 (d, J=15 Hz, 1H), 6.18 (s, 1H), 5.11 (s, 2H),3.30 (br s, 1H), 3.17 (s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (372 mg, 1.6mmol) in NMP (3 mL) in a 4 dram vial was added isoindoline (238 mg, 2mmol) and triethylamine (400 μL, 2.9 mmol). A cap was tightly fitted andthe reaction was heated at 85° C. O/N. The reaction was worked up bydiluting with EtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine(1×20 mL). The organic phase was dried with MgSO₄ filtered andconcentrated in vacuo. The crude material was purified by flash columnchromatography (9:1 Hex/EtOAc) to give 208 mg (41% yield) of6-bromo-4-(isoindolin-2-yl)benzo[c][1,2,5]oxadiazole. ¹H NMR (300 MHz,CDCl₃) δ=7.38 (m, 4H), 7.26 (s, 1H), 6.14 (s, 1H), 5.14 (s, 4H). To asolution of the afore mentioned material, (200 mg, 0.6 mmol) in DME (4mL)/Na₂CO₃ (0.9 mL) was added 3-formyl-phenylboronic acid (134 mg, 0.9mmol) and Pd(P(Ph)₃)₄ (35 mg). The flask was then fitted with a refluxcondenser, purged with argon and heated to 115° C. O/N. The reaction wasworked up by diluting with 1 M NaOH (40 mL) and extracting with EtOAc(3×20 mL). The organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo. The crude material was fused to SiO₂ (2 g) andpurified by flash column chromatography (2:1 DCM/Hex) to give 190 mg(92% yield). ¹H NMR (500 MHz, CDCl₃) δ=10.18 (s, 1H), 8.24 (m, 1H), 7.99(dm, J=8 Hz, 2H), 7.70 (t, J=7 Hz, 1H), 7.44 (m, 4H), 7.26 (s, 1H), 6.30(s, 1H), 5.25 (s, 4H). To a stirring solution of the afore mentionedmaterial, (190 mg, 0.55 mmol) and Rupert's reagent (150 mg, 1.1 mmol) inDCM (5 mL) at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30min at low temperature the cold bath was removed and the reaction wasallowed to come to RT. After 3 hours an excess of TBAF was added and thereaction was diluted with DCM. The organic phases were washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was passed through a plug of SiO₂ (DCM) andthen purified by flash column chromatography (2:1 DCM/Hex). ¹H NMR (500MHz, CDCl₃) δ=7.84 (s, 1H), 7.77 (dt, J=7 Hz, 2 Hz, 1H), 7.60 (m, 2H),7.43 (m, 4H), 7.23 (s, 1H), 6.25 (s, 1H), 5.31 (s, 4H), 5.2 (m, 1H),2.68 (s, 1H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(1.5615 g, 4.65 mmol) was dissolved in THF (45 mL) and cooled to −78° C.nBuLi (2.6 mL, 2.0 M solution of cyclohexane) was added dropwise and thesolution was stirred for 30 minutes at −78° C. DMF (0.54 mL, 7.0 mmol)was added and the reaction was stirred at −78° C. for 3 hours. Thisreaction was then quenched with saturated NH₄Cl(aq) and allowed toslowly warm to room temperature. This mixture was extracted with EtOAcand the combined organic layers were washed with H₂O (3×) brine, dried(Na₂SO₄), filtered and concentrated to give the crude aldehyde. Thismaterial was purified via 10% EtOAc/hexane column to afford 0.7248 g(55% yield) of aldehyde. This aldehyde (0.5615 g, 1.97 mmol) in THF (5mL) was added to a stirred suspension of NaH (0.104 g, 2.6 mmol) andtrimethyl phosponoacetate (0.31 mL, 2.17 mmol) in THF (20 mL) at 0° C.After the addition was complete the mixture was stirred overnight whilewarming to room temperature. After re-cooling to 0° C. the reaction wasquenched with saturated NH₄Cl (aq). This mixture was then extracted withEtOAc. The combined organic layers were washed with H₂O (3×), brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified via 20% EtOAc/hexane to give 0.5945 g (88% yield) of TRV-1402as the trans-isomer. ¹H NMR (500 MHz, CDCl3) δ=7.64 (d, J=15 Hz, 1H),7.25 (s, 1H), 7.23-7.21 (m, 2H), 7.03-7.00 (m, 2H), 6.46 (d, J=15 Hz,1H), 6.25 (s, 1H), 5.10 (s, 2H), 3.83 (s, 3H), 3.15 (s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (353 mg, 1.5mmol) in NMP (3 mL) in a 4 dram vial was added 3-hydroxyazetidinehydrochloride (180 mg, 1.65 mmol) and triethylamine (635 μL, 4.5 mmol).A cap was tightly fitted and the reaction was heated at 85° C. O/N.Reaction worked up by diluting with EtOAc (60 mL) and washing with 1MHCl (3×20 mL) and brine (1×20 mL). The organic phase was dried withMgSO₄ filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (DCM) to give 264 mg (65% yield)of 1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol. ¹H NMR (300MHz, CDCl₃) δ=7.23 (s, 1H), 5.95 (s, 1H), 4.92 (m, 1H), 4.59 (m, 2H),4.15 (m, 2H), 2.20 (d, J=6 Hz, 1H). To a stirring 0° C. solution of1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (480 mg, 2 mmol)in NMP (12 mL) was added MeI (1.4 g, 10 mmol) followed by NaH (200 mg,8.5 mmol). With the cold bath in place the reaction was allowed to cometo RT. After 16 hours the reaction was cautiously quenched with water,treated with saturated NH₄Cl and extracted into EtOAc (3×20 mL). Thecombined organics were washed with HCl (2M) followed by brine, driedwith MgSO₄ and concentrated in vacuo. The material purified by drysuction chromatography (1:1 DCM/Hex) to give 46 mg (71% yield). ¹H NMR(300 MHz, CDCl₃) δ=7.22 (d, J=1 Hz, 1H), 5.92 (s, br, 1H), 4.44 (m, 3H),4.16 (m, 2H), 3.37 (s, 3H). To a solution of TKW-I-92 (406 mg, 1.43mmol) in DME (7 mL)/Na₂CO₃ (2.1 mL) was added 3-formyl-phenylboronicacid (322 mg, 2.1 mmol) and Pd(P(Ph)₃)₄ (80 mg). The flask was thenfitted with a reflux condenser, purged with argon and heated to 115° C.O/N. The reaction was worked up by diluting with 1 M NaOH (40 mL) andextracting with EtOAc (3×20 mL). The organic phase was washed withbrine, dried with MgSO₄ and concentrated in vacuo. The crude materialwas purified by dry suction filtration (DCM) to give 411 mg of material.¹H NMR (500 MHz, CDCl₃) δ=10.11 (s, 1H), 8.12 (m, 1H), 7.93 (dm, J=8 Hz,1H), 7.88 (dm, J=8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.21 (m, 1H), 6.08 (m,1H), 4.56 (dd, J=10 Hz/5 Hz, 2H), 4.46 (m, 1H), 4.21 (dd, J=10 Hz/4 Hz,2H), 3.39 (s, 3H). To a stirring solution of TKW-I-93 (411 mg, 1.33mmol) and Rupert's reagent (378 mg, 2.7 mmol) in DCM (13 mL) at 0° C.was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 3 hours an excess of TBAF was added and the reactionwas diluted with DCM. The organic phases were washed with saturatedNH₄Cl, brine, and then dried with MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash column chromatography (DCM) to give477 mg (94% yield). ¹H NMR (500 MHz, CDCl₃) δ=7.72 (s, broad, 1H), 7.65(dt, J=7 Hz/2 Hz, 2H), 7.51 (m, 2H), 7.17 (d, J=1 Hz, 1H), 6.06 (s, 1H),5.12 (m, 1H), 4.53 (m, 2H), 4.45 (m, 1H), 4.18 (dm, J=10 Hz, 2H), 3.38(s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (355 mg, 1.52mmol) in NMP (3 mL) in a 4 dram vial was added N-methyl propargylamine(92 mg, 1.67 mmol) and triethylamine (635 μL, 4.5 mmol). A cap wastightly fitted and the reaction was heated at 85° C. O/N. Reactionworked up by diluting with EtOAc (60 mL) and washing with 1M HCl (3×20mL) and brine (1×20 mL). The organic phase was dried with MgSO₄ filteredand concentrated in vacuo. Due to the volatile nature of the SM thecrude material was only 50% converted. The mixture was used withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ=8.03 (s, 1H, SM), 7.55(s, 1H, SM), 7.41 (s, 1H), 6.35 (s, 1H), 4.66 (s, 2H), 3.24 (s, 3H),2.27 (s, 1H). To a solution of TKW-I-81 (180 mg, 0.7 mmol) in DME (3mL)/Na₂CO₃ (1.0 mL) was added 3-formyl-phenylboronic acid (152 mg, 1.0mmol) and Pd(P(Ph)₃)₄ (40 mg). The flask was then fitted with a refluxcondenser, purged with argon and heated to 115° C. O/N. The reaction wasworked up by diluting with 1 M NaOH (40 mL) and extracting with EtOAc(3×20 mL). The organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (9:1 Hex/EtOAc) to give 58 mg of material. ¹H NMR (500MHz, CDCl₃) δ=10.12 (s, 1H), 8.17 (m, 1H), 7.99 (dm, J=8 Hz, 1H), 7.96(dm, J=8 Hz, 1H), 7.39 (s, 1H), 6.54 (s, 1H), 4.71 (s, 2H), 3.31 (s,3H), 2.28 (s, 1H). To a stirring solution of TKW-I-87 (277 mg, 0.94mmol) and Rupert's reagent (400 mg, 2.8 mmol) in DCM (10 mL) at 0° C.was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 3 hours an excess of TBAF was added and the reactionwas diluted with DCM. The organic phases were washed with saturatedNH₄Cl, brine, and then dried with MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash column chromatography (50-80 DCM inHex). ¹H NMR (300 MHz, CDCl₃) δ=7.76 (m, 1H), 7.69 (m, 1H), 7.55 (m,2H), 7.34 (d, J=1 Hz, 1H), 6.55 (d, J=1 Hz, 1H), 5.14 (m, 1H), 4.68 (d,J=2 Hz, 2H), 3.30 (s, 3H), 2.69 (d, J=4 Hz, 1H), 2.29 (t, J=2 Hz, 1H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (388 mg, 1.66mmol) in NMP (3 mL) in a 4 dram vial was added cyclopropylamine (104 mg,1.83 mmol) and triethylamine (694 μL, 4.9 mmol). A cap was tightlyfitted and the reaction was heated at 85° C. O/N. Reaction worked up bydiluting with EtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine(1×20 mL). The organic phase was dried with MgSO₄ filtered andconcentrated in vacuo. The crude material was purified by flash columnchromatography (DCM) to give 264 mg (65% yield). ¹H NMR (500 MHz, CDCl₃)δ=7.32 (m, 1H), 6.60 (m, 1H), 5.46 (s, broad, 1H), 2.65 (m, 1H), 0.94(m, 2H), 0.74 (m, 2H). To a solution of TKW-I-88 (214 mg, 0.8 mmol) inDME (3 mL)/Na₂CO₃ (1.0 mL) was added 3-formyl-phenylboronic acid (240mg, 1.6 mmol) and Pd(P(Ph)₃)₄ (40 mg). The flask was then fitted with areflux condenser, purged with argon and heated to 115° C. O/N. Thereaction was worked up by diluting with 1 M NaOH (40 mL) and extractingwith EtOAc (3×20 mL). The organic phase was washed with brine, driedwith MgSO₄ and concentrated in vacuo. The crude material was fused toSiO₂ (3 g) and purified by flash column chromatography (9:1 Hex/EtOAc)to give 100 mg (42% yield) of material. ¹H NMR (300 MHz, CDCl₃) δ=10.13(s, 1H), 8.19 (m, 1H), 7.94 (m, 2H), 7.69 (t, J=7 Hz, 1H), 7.32 (m, 1H),6.83 (m, 1H), 3.57 (s, 3H), 2.77 (m, 1H), 1.01 (m, 2H), 0.76 (m, 2H). Toa stirring solution of TKW-I-91 (277 mg, 0.94 mmol) and Rupert's reagent(400 mg, 2.8 mmol) in DCM (10 mL) at 0° C. was added TBAF (0.1 mL, 1 MTHF, 0.1 mmol). After 30 min at low temperature the cold bath wasremoved and the reaction was allowed to come to RT. After 3 hours anexcess of TBAF was added and the reaction was diluted with DCM. Theorganic phases were washed with saturated NH₄Cl, brine, and then driedwith MgSO₄ and concentrated in vacuo. The crude material purified byflash column chromatography (10-15% EtOAc in Hex) to give 100 mg (80%yield). ¹H NMR (300 MHz, CDCl₃) δ=7.77 (s, 1H), 7.68 (m, 1H), 7.53 (m,2H), 7.28 (m, 1H), 6.82 (d, J=1 Hz, 1H), 5.13 (m, 1H), 3.54 (s, 3H),2.67 (m, 2H), 0.96 (m, 2H), 0.75 (m, 2H).

To a solution of 1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol(260 mg, 0.9 mmol) in DME (6 mL)/Na₂CO₃ (1.5 mL) was added3-formyl-phenylboronic acid (225 mg, 0.9 mmol) and Pd(P(Ph)₃)₄ (45 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by diluting with 1 MNaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo to give277 mg. The crude material was a single spot by TLC and used withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ=10.12 (s, 1H), 8.14 (s,1H), 7.98 (dm, J=7 Hz, 1H), 7.93 (dm, J=8 Hz, 1H), 7.70 (t, J=7 Hz, 1H),7.24 (s, 1H), 6.11 (s, 1H), 4.95 (m, 1H), 4.63 (m, 2H), 4.19 (2H), 2.28(m, 1H). To a stirring solution of aldehyde (277 mg, 0.94 mmol) andRupert's reagent (400 mg, 2.8 mmol) in DCM (10 mL) at 0° C. was addedTBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30 min at low temperature thecold bath was removed and the reaction was allowed to come to RT. After3 hours an excess of TBAF was added and the reaction was diluted withDCM. The organic phases were washed with saturated NH₄Cl, brine, andthen dried with MgSO₄ and concentrated in vacuo. The crude materialpurified by flash column chromatography (40% EtOAc in Hex) to give 147mg (42% yield) of TRV-1406. ¹H NMR (500 MHz, CDCl₃) δ=7.76 (s, 1H), 7.69(dt, J=7 Hz, 2 Hz, 1H), 7.57 (m, 2H), 7.23 (s, 1H), 6.12 (s, 1H), 5.16(q, J=6 Hz, 1H), 4.96 (m, 1H), 4.65 (dd, J=10 Hz/6 Hz, 2H), 4.20 (dd,J=10 Hz/6 Hz, 2H), 2.71 (s, broad, 1H), 2.22 (s, broad, 1H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.2959 g, 0.88 mmol) was dissolved in THF (5 mL) and cooled to −78° C.nBuLi (0.51 mL, 1.01 mmol, 2.0 M solution in cyclohexane) was addeddropwise and the solution was stirred for 20 minutes at −78° C. I₂ (1.3mL, 1.0 M solution in THF) was added and the solution was allowed toslowly warm to 0° C. overnight. The reaction was quenched with saturatedNH₄Cl (aq) and extracted with EtOAc. The combined organic layers werewashed with H₂O (3×), brine, dried (Na₂SO₄), filtered and concentrated.The crude material was purified via 3% EtOAc/hexane column to provide0.1381 g (41% yield, 89% c.p.) of aryl iodide 8. The aryl iodide (0.1332g, 0.348 mmol) and methyl propiolate (0.12 mL, 1.39 mmol) were added toa tube. The tube was evacuated and purged with argon (3×). ThePd(PPh₃)₂Cl₂ (0.0122 g, 0.0174 mmol), CuI (0.0066 g, 0.0348 mmol) andK₂CO₃ (0.0962 g, 0.696 mmol) were added. The tube was sealed and heatedto 65° C. overnight. Upon cooling to room temperature the mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was washed with H₂O (3×), brine, dried (Na₂SO₄), filtered andconcentrated. The crude material was purified via 10% EtOAc/hexanecolumn to afford 0.0154 g (13% yield) of TRV-1408. ¹H NMR (500 MHz,CDCl3) δ=7.42 (s, 1H), 7.21-7.18 (m, 2H), 7.03-7.00 (m, 2H), 6.17 (s,1H), 5.11 (s, 2H), 3.86 (s, 3H), 3.13 (s, 3H).

To a stirred solution of TRV-1402 (0.5283 g, 1.55 mmol) in DCM (10 mL)at −78° C. was added DIBAL (3.6 mL, 1.0 M solution in hexane) dropwise.Once the addition was complete the reaction was warmed to −40° C. andstirred under argon until complete consumption of starting material.Quenched with a saturated solution of Rochelle's salt and stirred for 30minutes. This mixture was extracted with EtOAc. The combined organiclayers were washed with H₂O (3×), brine, dried (Na₂SO₄), filtered andconcentrated. The crude oil was purified via 50% EtOAc é hexane columnto afford 0.3740 g (77% yield) of TRV-1409 as an orange oil. ¹H NMR (500MHz, CDCl3) δ=7.23-7.21 (m, 2H), 7.03 (s, 1H), 7.02-6.98 (m, 2H), 6.64(d, J=15 Hz, 1H), 6.44 (dt, J=15, 5 Hz, 1H), 6.26 (s, 1H), 5.06 (s, 2H),4.38 (dd, J=5 Hz, 2H), 3.11 (s, 3H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.1444 g, 0.43 mmol) was dissolved in THF (5 mL) and cooled to −78° C.nBuLi (0.23 mL, 0.45 mmol, 2.0 M solution of cyclohexane) was addeddropwise and the mixture was stirred for 30 minutes. Methylchloroformate (0.050 mL, 0.65 mmol) was then added and the reaction wasallowed to slowly warm to room temperature. After re-cooling to 0° C.the reaction was quenched with saturated NH₄Cl (aq). This mixture wasthen extracted with EtOAc. The combined organic layers were washed withH₂O (3×), brine, dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified via 15% EtOAc/hexane to afford 0.0234 g (17%yield) of TRV-1410. ¹H NMR (500 MHz, CDCl3) δ=7.88 (d, J=5 Hz, 1H),7.22-7.19 (m, 2H), 7.03-6.98 (m, 2H), 6.75 (s, 1H), 5.12 (s, 2H), 3.95(s, 3H), 3.17 (s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (396 mg, 1.7mmol) in NMP (3 mL) in a 4 dram vial was added 3-hydroxypyrrolidinehydrochloride (230 mg, 1.83 mmol) and triethylamine (710 μL, 5.1 mmol).A cap was tightly fitted and the reaction was heated at 85° C. O/N.Reaction worked up by diluting with EtOAc (60 mL) and washing with 1MHCl (3×20 mL) and brine (1×20 mL). The organic phase was dried withMgSO₄ filtered and concentrated in vacuo. The crude aniline was usedwithout further purification. To a stirring 0° C. solution of aniline(480 mg, 1.7 mmol) in NMP (10 mL) was added MeI (1.06 mL mg, 17 mmol)followed by NaH (200 mg, 8.5 mmol). With the cold bath in place thereaction was allowed to come to RT. After 16 hours the reaction wascautiously quenched with water, treated with saturated NH₄Cl andextracted into EtOAc (3×20 mL). The combined organics were washed withHCl (2M) followed by brine, and then dried with MgSO₄ and concentratedin vacuo. The material obtained was used without further purification.To a solution of the afore mentioned ether (1.7 mmol) in DME (8mL)/Na₂CO₃ (2.5 mL) was added 3-formyl-phenylboronic acid (382 mg, 2.6mmol) and Pd(P(Ph)₃)₄ (80 mg). The flask was then fitted with a refluxcondenser, purged with argon and heated to 115° C. O/N. The reaction wasworked up by diluting with 1 M NaOH (40 mL) and extracting with EtOAc(3×20 mL). The organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (4:1 Hex/EtOAc) to give 415 mg of material. ¹H NMR (500MHz, CDCl₃) δ=10.11 (s, 1H), 8.15 (s, 1H), 7.91 (m, 2H), 7.64 (t, J=8Hz, 1H), 7.14 (s, 1H), 6.14 (s, 1H), 4.94 (m, 1H), 3.95 (m, 4H), 3.41(s, 3H), 2.17 (m, 2H). To a stirring solution of aldehyde (415 mg, 1.33mmol) and Rupert's reagent (365 μL, 2.6 mmol) in DCM (10 mL) at 0° C.was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 3 hours an excess of TBAF was added and the reactionwas diluted with DCM. The organic phases were washed with saturatedNH₄Cl, brine, and then dried with MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash column chromatography (10-30% EtOAcin Hex) to give 240 mg (48% yield) of TRV-1411, a 1:1:1:1 mixture ofdiastereomers due to the two chiral centers. ¹H NMR (500 MHz, DMSO-D₆)δ=7.90 (s, 1H), 7.82 (dm, J=7 Hz, 1H), 7.53 (m, 2H), 7.29 (s, 1H), 6.93(d, J=6 Hz, 1H), 6.29 (s, 1H), 5.28 (m, 1H), 4.18 (s, 1H), 3.87 (m, 3H),3.77 (m, 1H), 2.15 (m, 2H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (355 mg, 1.52mmol) in NMP (3 mL) in a 4 dram vial was addedN-methyl-N-(2-pyridinylmethyl)amine (204 mg, 1.67 mmol) andtriethylamine (400 μL, 2.9 mmol). A cap was tightly fitted and thereaction was heated at 85° C. O/N. Reaction worked up by diluting withEtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine (1×20 mL). Theorganic phase was dried with MgSO₄ filtered and concentrated in vacuo.The crude material was purified by flash column chromatography (4:1Hex/EtOAc) to give 293 mg (60% yield) of aniline To a solution of thisaniline (293 mg, 0.91 mmol) in DME (5 mL)/Na₂CO₃ (1.4 mL) was added3-formyl-phenylboronic acid (202 mg, 1.4 mmol) and Pd(P(Ph)₃)₄ (50 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by diluting with 1 MNaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudematerial was fused to SiO₂ (3 g) and purified by flash columnchromatography (4:1 Hex/EtOAc) to give 280 mg of aldehyde. ¹H NMR (500MHz, CDCl₃) δ=10.01 (s, 1H), 8.60 (dm, J=4 Hz, 1H), 8.09 (t, J=2H, 1H),7.93 (dt, J=7 Hz/2 Hz, 1H), 7.87 (dm, J=8 Hz, 1H), 7.64 (m, 2H), 7.28(m, 2H), 7.20 (m, 1H), 6.39 (s, 1H), 5.28 (s, 2H), 3.37 (s, 3H). To astirring solution of aldehyde (280 mg, 0.81 mmol) and Rupert's reagent(230 mg, 1.63 mmol) in DCM (10 mL) at 0° C. was added TBAF (0.1 mL, 1 MTHF, 0.1 mmol). After 30 min at low temperature the cold bath wasremoved and the reaction was allowed to come to RT. After 3 hours anexcess of TBAF was added and the reaction was diluted with DCM. Theorganic phases were washed with saturated NH₄Cl, brine, and then driedwith MgSO₄ and concentrated in vacuo. The crude material was purified byflash column chromatography (10% EtOAc in Hex) to give 120 mg (35%yield) of TRV-1412. ¹H NMR (500 MHz, DMSO-D₆) δ=8.51 (d, J=6 Hz, 1H),7.87 (s, 1H), 7.80 (dm, J=8 Hz, 1H), 7.74 (td, J=8 Hz/2 Hz, 1H), 7.57(m, 2H), 7.36 (s, 1H), 7.32 (d, J=8 Hz, 1H), 7.26 (m, 1H), 6.95 (d, J=5Hz, 1H), 5.27 (m, 3H), 3.36 (s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (360 mg, 1.54mmol) in NMP (3 mL) in a 4 dram vial was addedN-methyl-N-(3-pyridinylmethyl)amine (207 mg, 1.69 mmol) andtriethylamine (400 μL, 2.9 mmol). A cap was tightly fitted and thereaction was heated at 85° C. O/N. Reaction worked up by diluting withEtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine (1×20 mL). Theorganic phase was dried with MgSO₄ filtered and concentrated in vacuo.The crude material was purified by flash column chromatography (5% EtOAcin DCM) to give 247 mg (50% yield) of aniline. ¹H NMR (500 MHz, DMSO-D₆)δ=8.50 (d, J=2 Hz, 1H), 8.48 (dd, J=5 Hz/1 Hz, 1H), 7.64 (dm, J=8 Hz,1H), 7.52 (d, J=1 Hz, 1H), 7.35 (dd, J=8 Hz/5 Hz, 1H), 6.35 (m, 1H),5.17 (s, 2H), 3.21 (s, 3H). To a solution of aniline (247 mg, 0.77 mmol)in DME (4 mL)/Na₂CO₃ (1.1 mL) was added 3-formyl-phenylboronic acid (173mg, 1.2 mmol) and Pd(P(Ph)₃)₄ (40 mg). The flask was then fitted with areflux condenser, purged with argon and heated to 115° C. O/N. Thereaction was worked up by diluting with 1 M NaOH (40 mL) and extractingwith EtOAc (3×20 mL). The organic phase was washed with brine, driedwith MgSO₄ and concentrated in vacuo to give 312 mg of crude aldehyde.To a stirring solution of aldehyde (0.77 mmol) and Rupert's reagent (400mg, 2.8 mmol) in DCM (8 mL) at 0° C. was added TBAF (0.1 mL, 1 M THF,0.1 mmol). After 30 min at low temperature the cold bath was removed andthe reaction was allowed to come to RT. After 3 hours an excess of TBAFwas added and the reaction was diluted with DCM. The organic phases werewashed with saturated NH₄Cl, brine, dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(2% MeOH in DCM). ¹H NMR (300 MHz, CDCl₃) δ=8.51 (m, 2H), 7.70-7.55 (m,3H), 7.50-7.45 (m, 2H), 7.28 (m, 1H), 7.25 (m, 1H), 6.35 (s, 1H), 5.14(m, 3H), 4.24 (s, broad, 1H), 3.19 (s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (357 mg, 1.5mmol) in NMP (3 mL) in a 4 dram vial was added 4-methoxybenzylamine (230mg, 1.65 mmol) and triethylamine (400 μL, 2.9 mmol). A cap was tightlyfitted and the reaction was heated at 85° C. O/N. Reaction worked up bydiluting with EtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine(1×20 mL). The organic phase was dried with MgSO₄ filtered andconcentrated in vacuo. The crude aniline was used without furtherpurification. To a stirring 0° C. solution of aniline (220 mg, 0.6 mmol)in NMP (5 mL) was added NaH (151 mg, 6.3 mmol). After the evolution ofgas had ceased MeI (446 mg, 3.1 mmol) was added dropwise. With the coldbath in place the reaction was allowed to come to RT. After 16 hours thereaction was cautiously quenched with water, treated with saturatedNH₄Cl and extracted into EtOAc (3×20 mL). The combined organics werewashed with brine, dried with MgSO₄ and concentrated in vacuo. Theaniline obtained was used without further purification. To a solution ofaniline (0.6 mmol) in DME (4 mL)/Na₂CO₃ (1.0 mL) was added3-formyl-phenylboronic acid (142 mg, 0.9 mmol) and Pd(P(Ph)₃)₄ (45 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by diluting with 1 MNaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo to give220 mg of crude material. ¹H NMR (300 MHz, CDCl₃) δ=10.1 (s, 1H), 8.1(s, 1H), 7.9 (m, 2H), 7.7 (m, 1H), 7.2 (m, 2H), 6.9 (d, J=6 Hz, 2H), 6.4(m, 1H), 5.1 (s, 2H), 3.8 (s, 3H), 3.2 (s, 3H). To a stirring solutionof aldehyde (220 mg, 0.59 mmol) and Rupert's reagent (168 mg, 1.2 mmol)in DCM (6 mL) at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After30 min at low temperature the cold bath was removed and the reaction wasallowed to come to RT. After 3 hours an excess of TBAF was added and thereaction was diluted with DCM. The organic phases were washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(20% EtOAc in Hex). ¹H NMR (300 MHz, CDCl₃) δ=7.7 (s, 1H), 7.6 (dt, J=7Hz, 1 Hz, 1H), 7.5 (m, 2H), 7.19 (m, 3H), 6.8 (d, J=8 Hz, 2H), 6.3 (s,1H), 5.1 (m, 1H), 5.0 (s, 2H), 3.8 (s, 3H), 3.2 (s, 3H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (345 mg, 1.5mmol) in NMP (3 mL) in a 4 dram vial was added 3,5-dimethoxybenzylamine(272 mg, 1.6 mmol) and triethylamine (600 μL, 4.3 mmol). A cap wastightly fitted and the reaction was heated at 85° C. O/N. Reactionworked up by diluting with EtOAc (60 mL) and washing with 1M HCl (3×20mL) and brine (1×20 mL). The organic phase was dried with MgSO₄ filteredand concentrated in vacuo. The crude material was used without furtherpurification. To a stirring 0° C. solution of aniline (1.5 mmol) in NMP(5 mL) was added NaH (211 mg, 8.8 mmol). After the evolution of gas hadceased MeI (570 mg, 4 mmol) was added dropwise. With the cold bath inplace the reaction was allowed to come to RT. After 16 hours thereaction was cautiously quenched with water, treated with saturatedNH₄Cl and extracted into EtOAc (3×20 mL). The combined organics werewashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudematerial was fused to SiO₂ and flashed (10% EtOAc in Hex) to give 163 mgof material. To a solution of aniline (165 mg, 0.44 mmol) in DME (4mL)/Na₂CO₃ (0.7 mL) was added 3-formyl-phenylboronic acid (98 mg, 0.9mmol) and Pd(P(Ph)₃)₄ (40 mg). The flask was then fitted with a refluxcondenser, purged with argon and heated to 115° C. O/N. The reaction wasworked up by diluting with 1 M NaOH (40 mL) and extracting with EtOAc(3×20 mL). The organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo to give 277 mg. The crude material was usedwithout further purification. To a stirring solution of aldehyde (277mg, 0.4 mmol) and Rupert's reagent (125 mg, 0.8 mmol) in DCM (4 mL) at0° C. was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 3 hours an excess of TBAF was added and the reactionwas diluted with DCM. The organic phases were washed with saturatedNH₄Cl, brine, and then dried with MgSO₄ and concentrated in vacuo. Thecrude material was fused to SiO₂ (3 g) purified by flash columnchromatography (10-20% EtOAc in Hex). ¹H NMR (500 MHz, CDCl₃) δ=7.7 (s,1H), 7.6 (dt, 7 Hz, 1 Hz, 2H), 7.5 (m, 2H), 7.2 (s, 1H), 6.4 (m, 1H),6.3 (m, 2H), 5.1 (m, 1H), 5.0 (s, 2H), 3.7 (s, 3H), 3.3 (s, 3H), 2.7 (s,broad, 1H)

TRV-1397 (0.0768 g, 0.22 mmol) was dissolved in THF (5 mL) and cooled to0° C. NaH (0.0132 g, 0.33 mmol) was added and the suspension was stirredfor 30 minutes. Iodomethane (0.03 mL, 0.44 mmol) was then added and thereaction was stirred overnight while warming to room temperature. Themixture was then re-cooled to 0° C. and quenched with saturated ammoniumchloride. The mixture was extracted with EtOAc. The combined organicextracts were washed with water, brine, dried (Na₂SO₄), filtered andconcentrated. The crude material was then purified via a 10%EtOAc/hexane column to afford 0.0259 g (32% yield) of TRV-1416 as orangeoil. ¹H NMR (500 MHz, CDCl3) δ=7.30-7.27 (m, 2H), 7.23 (s, 1H),7.07-7.04 (m, 2H), 6.22 (s, 1H), 5.11 (s, 2H), 4.52 (q, J=5 Hz, 1H),3.50 (s, 3H), 3.20 (s, 3H).

To a solution of oxalyl chloride (0.032 mL, 0.37 mmol) in DCM (1 mL) at−78° C. was added a solution of DMSO (0.024 mL, 0.34 mmol) in DCM (1.1mL). The solution was stirred for 5 minutes and then a solution ofTRV-1397 (0.1097 g, 0.31 mmol) in DCM (1.0 mL) was added and the mixturewas stirred an additional 15 minutes. TEA (0.22 mL, 1.55 mmol) was addedin one portion, the reaction was stirred for 10 minutes at −78° C. andthen allowed to warm to room temperature. The mixture was then dilutedwith water and ethyl acetate. The layers were separated and the aqueouslayer was back-extracted. The combined organic layers were washed withbrined, dried (Na₂SO₄), filtered and concentrated to give the crudetrifluoroketone. This material was then purified via flashchromatography (30% EtOAc/hexane) to give 0.0356 g (32% yield) ofTRV-1417 as orange oil. ¹H NMR (500 MHz, CDCl3) δ=7.93 (s, 1H),7.23-7.20 (m, 2H), 7.04-7.00 (m, 2H), 6.67 (s, 1H), 5.16 (s, 2H), 3.23(s, 3H).

TRV-1421 (0.3511 g, 1.17 mmol) was dissolved in DCM (50 mL) andDess-Martin reagent (1.4845 g, 3.5 mmol) was added. The reaction wasstirred for 40 minutes and then was quenched with saturated NaHCO₃ (aq)and excess Na₂S₂O₃. The mixture was stirred until all the solidsdissolved and then was extracted several times with DCM. The combinedorganic extracts were washed with saturated NaHCO₃, dried (NA₂SO₄),filtered and concentrated. The crude material was purified via 10%EtOAc/hexane column to afford 0.2322 g (66% yield) of TRV-1418 as orangesolid. ¹H NMR (500 MHz, CDCl3) δ=7.74 (s, 1H), 7.22-7.19 (m, 2H),7.02-6.97 (m, 2H), 6.74 (s, 1H), 3.17 (s, 3H), 2.65 (s, 3H).

To a stirring solution of6-bromo-4-(isoindolin-2-yl)benzo[c][1,2,5]oxadiazole (158 mg, 0.3 mmol)in THF (5 mL) at −78° C. was added n-BuLi (0.25 mL, 2 M). After stirringfor 30 min at low temperature oxatenanone (72 mg, 1 mmol) dissolved inTHF (4 mL). The cold bath was removed and the reaction was allowed tocome to RT and monitored by TLC. The reaction was worked up with diluteHCl and extracted into EtOAc (3×20 mL). The organic phase was dried withMgSO₄ and concentrated in vacuo. The crude material was fused to SiO₂ (3g) and purified by flash column chromatography (DCM modified with MeOH)to give 40 mg of material. ¹H NMR (300 MHz, DMSO-D₆) δ=7.5 (m, 2H), 7.4(m, 2H), 7.2 (s, 1H), 6.6 (s, 1H) 6.5 (s, 1H), 6.5 (s, 1H), 5.1 (s, 4H),4.8 (m, 4H).

To a stirring solution of6-bromo-4-(isoindolin-2-yl)benzo[c][1,2,5]oxadiazole (98 mg, 0.3 mmol)in THF (3 mL) at −78° C. was added n-BuLi (0.15 mL, 2 M). After stirringfor 30 min at low temperature dry DMF (0.5 mL) was added and thereaction was stirred for an additional hour before it was quenched withMeOH followed by HCl (4 M). The reaction was allowed to come to RT,diluted with water and extracted into DCM (3×20 mL). The organic phasewas dried with MgSO₄ and concentrated in vacuo. The crude material wasfused to SiO₂ (3 g) and purified by flash column chromatography (1:1DCM/Hex) to give 71 mg of material. To a stirring solution of aldehyde(71 mg, 0.26 mmol) and Rupert's reagent (74 mg, 0.52 mmol) in DCM (3 mL)at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 3 hours an excess of TBAF was added and the reactionwas diluted with DCM. The organic phases were washed with saturatedNH₄Cl, brine, and then dried with MgSO₄ and concentrated in vacuo. Thecrude material purified by flash column chromatography (DCM). ¹H NMR(500 MHz, DMSO-D₆) δ=7.50 (m, 2H), 7.37 (m, 2H), 7.27 (s, 1H), 7.11 (d,J=5 Hz, 1H), 6.32 (s, 1H), 5.29 (m, 1H), 5.09 (s. 4H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.8514 g, 2.53 mmol) was dissolved in THF (25 mL) and cooled to −78° C.nBuLi (1.3 mL, 2.0 M solution in cyclohexane) was added dropwise at −78°C. and the reaction was then stirred for 15-20 minutes. Acetaldehyde(0.21 mL, 3.8 mmol) were then added and the reaction was allowed toslowly warm to room temperature. The solution was re-cooled to 0° C. andquenched with saturated ammonium chloride. The mixture was extractedwith EtOAc. The combined organic extracts were washed with water, brine,dried (Na₂SO₄), filtered and concentrated. The crude material was thenpurified via a 40% EtOAc/hexane column to produce 0.5340 g (70% yield)of TRV-1421 as orange oil. ¹H NMR (500 MHz, CDCl3) δ=7.24-7.21 (m, 2H),7.10 (s, 1H), 7.02-6.98 (m, 2H), 6.16 (s, 1H), 5.06 (s, 2H), 4.87 (q,J=5 Hz, 1H), 3.11 (s, 3H), 1.90 (s, 1H), 1.51 (d, J=5 Hz, 3H).

TRV-1421 (0.1381 g, 0.458 mmol) was dissolved in THF (5 mL) and cooledto 0° C. NaH (0.0275 g, 0.687 mmol) was added and the suspension wasstirred for 30 minutes. Iodomethane (0.06 mL, 0.916 mmol) was then addedand the reaction was allowed to warm to room temperature. The solutionwas re-cooled to 0° C. and quenched with saturated ammonium chloride.The mixture was extracted with EtOAc. The combined organic extracts werewashed with water, brine, dried (Na₂SO₄), filtered and concentrated. Thecrude material was then purified via a 10% EtOAc/hexane column to afford0.1243 g (86% yield) of TRV-1422 as yellow oil. ¹H NMR (500 MHz, CDCl3)δ=7.25-7.23 (m, 2H), 7.02 (s, 1H), 7.02-6.98 (m, 2H), 6.14 (s, 1H), 5.07(d, J-15 Hz, 1H), 5.03 (d, J=15 Hz, 1H), 4.27 (q, J=5 Hz, 1H), 3.26 (s,3H), 3.12 (s, 3H), 1.44 (d, J=5 Hz, 3H).

To a solution of 6-bromo-4-(isoindolin-2-yl)benzo[c][1,2,5]oxadiazole(647 mg, 2.0 mmol) in DME (10 mL)/Na₂CO₃ (3 mL) was added3-acetyl-phenylboronic acid (500 mg, 0.9 mmol) and Pd(P(Ph)₃)₄ (90 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by diluting with 1 MNaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudematerial was dissolved in DCM and eluted through a short SiO₂ plug togive 456 mg of material which was suitable for further reactions. ¹H NMR(300 MHz, CDCl₃) δ=8.3 (m, 1H), 8.0 (d, J=8 Hz, 1H), 7.8 (d, J=8 Hz,1H), 7.6 (t, J=8 Hz, 1H), 7.4 (m, 4H), 7.2 (s, 1H), 6.2 (s, 1H), 5.1 (s,4H), 2.7 (s, 3H). To a stirring solution of ketone (222 mg, 0.6 mmol)dissolved in THF (4 mL) at 0° C. was added MeMgBr (0.9 mL, 0.9 mmol).After 30 minutes at low temperature the reaction was warmed to RT andquenched with dilute HCl and extracted into EtOAc (3×20 mL). The organicphase was dried with MgSO₄ and concentrated in vacuo. The crude materialwas purified by flash column chromatography (DCM). ¹H NMR (300 MHz,CDCl₃) δ=7.8 (m, 1H), 7.5 (m, 2H0, 7.4-7.3 (m, 5H), 7.2 (s, 1H), 5.1 (s,4H), 1.0 (s, 1H), 1.6 (s, 6H).

To a solution of 6-bromo-4-(isoindolin-2-yl)benzo[c][1,2,5]oxadiazole(647 mg, 2.0 mmol) in DME (10 mL)/Na₂CO₃ (3 mL) was added3-acetyl-phenylboronic acid (500 mg, 0.9 mmol) and Pd(P(Ph)₃)₄ (90 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by diluting with 1 MNaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudematerial was dissolved in DCM and eluted through a short SiO₂ plug togive 456 mg of material which was suitable for further reactions. ¹H NMR(300 MHz, CDCl₃) δ=8.3 (m, 1H), 8.0 (d, J=8 Hz, 1H), 7.8 (d, J=8 Hz,1H), 7.6 (t, J=8 Hz, 1H), 7.4 (m, 4H), 7.2 (s, 1H), 6.2 (s, 1H), 5.1 (s,4H), 2.7 (s, 3H). To a stirring solution of ketone (230 mg, 0.65 mmol)dissolved in MeOH/THF at 0° C. was added NaBH₄ (80 mg, 2 mmol). Once theinitial exothermic reaction had subsided the cold bath was removed andthe reaction was allowed to come to RT. The reaction was stirred at RTfor 1 hour and then poured onto water, after 30 min the reaction wasacidified and extracted into EtOAc (3×20 mL). The organic phase wasdried with MgSO₄ and concentrated in vacuo. The crude material waspurified by flash column chromatography (DCM). ¹H NMR (300 MHz, CDCl₃)δ=7.7 (s, 1H), 7.6 (dt, J=10 Hz, 1 Hz), 7.5-7.3 (m, 6H), 7.1 (s, 1H),6.2 (s, 1H), 5.2 (s, 4H), 5.0 (m, 1H), 1.9 (m, 1h), 1.5 (d, J=6 Hz, 3H).

TRV-1418 (0.1195 g, 0.399 mmol) was dissolved in THF (5 mL) and cooledto 0° C. MeMgBr (0.52 mL, 1.0 M solution in Bu₂O) was added dropwise andthe reaction was stirred until complete by TLC. The solution wasre-cooled to 0° C. and quenched with saturated ammonium chloride. Themixture was extracted with EtOAc. The combined organic extracts werewashed with water, brine, dried (Na₂SO₄), filtered and concentrated. Thecrude material was then purified via two consecutive 30% EtOAc/hexanecolumns to afford 0.0626 g (50% yield) of TRV-1425 as an orange oil inapproximately 90% cp. ¹H NMR (500 MHz, CDCl3) δ=7.23-7.20 (m, 2H), 7.19(s, 1H), 7.02-6.95 (m, 2H), 6.33 (s, 1H), 5.04 (s, 2H), 3.12 (s, 3H),1.59 (s, 6H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (347 mg, 1.49mmol) in NMP (3 mL) in a 4 dram vial was added benzenethiol (104 mg,1.83 mmol) and triethylamine (400 μL, 2.8 mmol). A cap was tightlyfitted and the reaction was heated at 85° C. O/N. Reaction worked up bydiluting with EtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine(1×20 mL). The organic phase was dried with MgSO₄ filtered andconcentrated in vacuo. The crude material was purified by flash columnchromatography (DCM) to give 264 mg (65% yield). ¹H NMR (500 MHz, CDCl₃)δ=7.8 (m, 1H), 7.6 (m, 2H), 7.5 (m, 3H), 6.7 (m, 1H). To a solution ofthioether (220 mg, 0.7 mmol) in DME (6 mL)/Na₂CO₃ (1.5 mL) was added3-acetyl-phenylboronic acid (185 mg, 1.1 mmol) and Pd(P(Ph)₃)₄ (75 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by diluting with 1 MNaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudematerial was purified by pushing through a SiO₂ plug with DCM. ¹H NMR(500 MHz, CDCl₃) δ=8.0 (s, 1H), 7.9 (m, 1H), 7.7 (s, 1H), 7.6 (m, 3H),7.5 (m, 1H), 7.5 (m, 3H), 7.1 (m, 1H), 2.6 (s, 3H). To a stirringsolution of ketone dissolved in MeOH/THF at 0° C. was added NaBH₄ (80mg, 2 mmol). Once the initial exothermic reaction had subsided the coldbath was removed and the reaction was allowed to come to RT. Thereaction was stirred at RT for 1 hour and then poured onto water, after30 min the reaction was acidified and extracted into EtOAc (3×20 mL).The organic phase was dried with MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash column chromatography (DCM). ¹H NMR(500 MHz, CDCl₃) δ=7.7 (d, J=1 Hz, 1H), 7.6 (m, 2H), 7.5-7.3 (m, 7H),7.1 (d, J=1 Hz, 1H), 4.9 (m, 1H), 1.8 (d, J=3 Hz, 1H), 1.5 (d, J=6 Hz,3H).

TRV-1409 (0.2077 g, 0.663 mmol) was dissolved in DCM (37 mL) and thenDMP (0.8436 g, 1.99 mmol) was added in one portion. The reaction wasstirred for 3 hours and then quenched with saturated NaHCO₃ (aq) andexcess Na₂S₂O₃. This mixture was stirred until all the solids dissolvedand then extracted with DCM. The combined organic layers were dried(Na₂SO₄), filtered and concentrated to afford the crude aldehyde.Purification via flash chromatography (20% EtOAc/hexane) afforded 0.0556g (27% yield) of the aldehyde 4. This aldehyde (0.0532 g, 0.171 mmol)was dissolved in THF (5 mL) and cooled to 0° C. MeMgBr (0.19 mL, 1.0 Msolution in Et₂O) was added dropwise and the reaction was stirred untilcomplete by TLC. The reaction was then quenched with NH₄Cl and extractedwith EtOAc. The combined organic extracts were washed with water, brine,dried (Na₂SO₄), filtered and concentrated. The crude material was thenpurified with flash chromatography to afford 0.0262 g (47% yield) ofTRV-1427 as orange oil. ¹H NMR (500 MHz, CDCl3) δ=7.23-7.21 (m, 2H),7.03-6.99 (m, 3H), 6.59 (d, J=15 Hz, 1H), 6.34 (dd, J=15, 5 Hz, 1H),6.26 (s, 1H), 4.54 (m, 1H), 3.10 (s, 3H), 1.62 (d, J=5 Hz, 1H), 1.40 (d,J=10 Hz, 3H).

In a sealed vial 4,6-dibromobenzo[c][1,2,5]oxadiazole (2.2 g, 8 mmol)was combined with, (888 mg, 8.8 mmol), Et₃N (3.3 mL, 24 mmol), and NMP(13 mL). The mixture was heated to 85° C. for 2 days. At this time thereaction was diluted with 1 M NaOH (150 mL) and the insoluble materialwas removed by filtration. The desired compound was precipitated by theaddition of HCl (conc.) to the aqueous layer and isolated by vacuumfiltration to give1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidine-3-carboxylic acid (1.7g), which was used without further purification. The acid (1.5 g, 5mmol) was dissolved in THF (50 mL) and cooled to 0° C. To this was addedBH₃-THF (10 mL, 10 mmol). The reaction was allowed to come to roomtemperature overnight. The next day the reaction was quenched with AcOHand extracted into EtOAc. The organic layer was washed with 1 M NaOHuntil the washings remained litmus blue and then concentrated in vacuo.The crude material was fused to SiO₂ and purified by flash columnchromatography (3:2 Hex:EtOAc) to give 800 mg of(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)methanol (56%yield). ¹H NMR (500 MHz, CDCl₃) δ=7.05 (s, 1H), 6.11 (s, 1H), 5.30 (s,1H), 4.11 (t, J=8 Hz, 2H), 3.85 (m, 4H), 3.00 (m, 1H). To a solution ofthe afore mentioned alcohol (400 mg, 1.4 mmol) in DME (7 mL)/Na₂CO₃ (2.1mL) was added 3-formyl-phenylboronic acid (315 mg, 2.1 mmol) andPd(P(Ph)₃)₄ (50 mg). The flask was then fitted with a reflux condenser,purged with argon and heated to 115° C. O/N. The reaction was worked upby pouring into 1 M NaOH (150 mL) and isolating the resultant solids byvacuum filtration. The crude material was purified by plugging throughSiO₂ (50% EtOAc in Hex) to give 350 mg of material which was used as is.To a stirring solution of aldehyde (400 mg, 1.4 mmol) and Rupert'sreagent (483 mg, 3.3 mmol) in DCM (13 mL) at 0° C. was added TBAF (0.1mL, 1 M THF, 0.2 mmol). After 30 min at low temperature the cold bathwas removed and the reaction was allowed to come to RT. After stirringovernight an excess of TBAF was added and the reaction was diluted withDCM. The organic phases were washed with saturated NH₄Cl, brine, andthen dried with MgSO₄ and concentrated in vacuo. The crude material waspurified by flash column chromatography (30% EtOAc in Hex) to give 150mg (34% yield). ¹H NMR (500 MHz, CDCl₃) δ=7.72-7.66 (m, 2H), 7.5 (m,2H), 7.14 (s, 1H0, 6.04 (s, 1H), 5.11 (m, 1H), 4.41 (t, J=8 Hz, 2H),4.15 (dd, 2H), 3.93 (d, J=5 Hz, 2H), 3.06 1H), 2.82 (s, broad), 1.63 (s,broad).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (574 mg, 2.1 mmol)was dissolved in DCM (25 mL) and cooled to −78° C. and DAST (421 uL, 3.2mmol) was added dropwise and the cold bath was removed. After 2 h atroom temperature the reaction was cooled to 0° C. and quenched withMeOH. The reaction mixture was then diluted with water and extractedwith DCM. The combined extracts were dried (MgSO₄) and concentrated invacuo. The residue was purified by flash column chromatography (50% DCMin Hex) to give product as a yellow solid (160 mg, 27% yield). ¹H NMR(500 MHz, CDCl₃) δ=7.27 (s, 1H), 5.96 (s, 1H), 5.51 (dm, ²J_(HF)=57 Hz,1H), 4.56 (m, 2H), 4.42 (dm, ³J_(HF)=23 Hz, 2H). To a solution ofaniline (330 mg, 1.2 mmol) in DME (7 mL)/Na₂CO₃ (1.8 mL) was added3-formyl-phenylboronic acid (270 mg, 1.9 mmol) and Pd(P(Ph)₃)₄ (50 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by plugging through SiO₂ (20% EtOAc in Hex) andused without further purification. To a stirring solution of aldehyde(about 1.0 mmol) and Rupert's reagent (348 mg, 2.0 mmol) in DCM (13 mL)at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.2 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After stirring overnight an excess of TBAF was added and thereaction was diluted with DCM. The organic phases were washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(25% EtOAc in Hex) to give 300 mg (80% yield). ¹H NMR (500 MHz, CDCl₃)δ=7.72 (s, 1H), 7.66 (dm, J=10 Hz, 1H), 7.51 (m, 2H), 7.23 (s, 1H), 6.12(s, 1H), 5.53 (dm, ²J_(HF)=56 Hz, 1H), 5.14 (m, 1H), 4.64 (m, 2H), 4.42(ddm, J=23 Hz/10 Hz, 2H), 2.73 (s, 1H).

TRV-1402 (0.1992 g, 0.58 mmol) was dissolved in THF (10 mL) and cooledto −78° C. MeLi (0.80 mL, 1.6 M solution in Et₂O) was added dropwise andthe reaction was allowed to warm to room temperature overnight. Themixture was then re-cooled to 0° C. and quenched with saturated ammoniumchloride. This mixture was extracted three times with EtOAc. Thecombined organic extracts were washed with water, brine, dried (Na₂SO₄),filtered and concentrated to give the crude alcohol. This material wasthen purified via chromatography (30% EtOAc/hexane) to afford 0.0843 g(43% yield) of orange oil. ¹H NMR (500 MHz, CDCl3) δ=7.23-7.21 (m, 2H),7.03 (s, 1H), 7.02-6.98 (m, 2H), 6.61 (d, J=15 Hz, 1H), 6.42 (d, J=15Hz, 1H), 6.25 (s, 1H), 5.08 (s, 2H), 3.10 (s, 3H), 1.45 (s, 6H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.2771 g, 0.82 mmol) was dissolved in THF (10 mL) and cooled to −78° C.nBuLi (0.43 mL, 2.0 M solution in cyclohexane) was added dropwise andthe mixture was stirred for 30 minutes before addingN,N-dimethylcarbamyl chloride (0.10 mL, 1.1 mmol) dropwise. The mixturewas then allowed to warm to room temperature overnight. The mixture wasthen re-cooled to 0° C. and quenched with saturated ammonium chloride.This mixture was extracted three times with EtOAc. The combined organicextracts were washed with water, brine, dried (Na₂SO₄), filtered andconcentrated to give the crude amide. Final purification of thismaterial was with a 50% EtOAc/hexane column to afford 16.6 mg (6.2%yield) of orange oil. ¹H NMR (500 MHz, CDCl3) δ=7.23-7.20 (m, 2H), 7.08(s, 1H), 7.03-6.99 (m, 2H), 6.12 (s, 1H), 5.11 (s, 2H), 3.14 (s, 3H),3.12 (s, 3H), 3.01 (s, 3H).

In a sealed vial 4,6-dibromobenzo[c][1,2,5]oxadiazole (834 mg, 3 mmol)was combined with azetidine hydrochloride (309 mg, 3.3 mmol), Et₃N (1.25mL, 9 mmol), and NMP (6 mL). The mixture was heated to 85° C. for 2days. The crude material was precipitated by pouring the reactionmixture into water (150 mL). The crude material was plugged through SiO₂(10% EtOAc in Hex) to give (540 mg) an orange solid which NMR showed tobe a 2:1 mixture of starting material and4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole. ¹H NMR (500 MHz,CDCl₃) δ=7.05 (s, 1H), 5.85 (s, 1H), 4.33 (m, 4H), 2.53 (m, 2H). To asolution of 4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole (322 mg,1.27 mmol) in DME (7 mL)/Na₂CO₃ (2.0 mL) was added3-formyl-phenylboronic acid (286 mg, 1.9 mmol) and Pd(P(Ph)₃)₄ (50 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 115° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by plugging through SiO₂ (DCM) to give 280 mg ofmaterial which was used as is. To a stirring solution of the aldehyde(411 mg, 1.33 mmol) and Rupert's reagent (378 mg, 2.7 mmol) in DCM (13mL) at 0° C. was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After 30 min atlow temperature the cold bath was removed and the reaction was allowedto come to RT. After 3 hours an excess of TBAF was added and thereaction was diluted with DCM. The organic phases were washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(DCM) to give 477 mg (94% yield). ¹H NMR (500 MHz, CDCl₃) δ=7.72 (s,1h), 7.66 (m, 1H), 7.52 (m, 2H), 7.13 (s, 1H), 6.01 (s, 1H), 5.12 (q,J=7 Hz, 1H), 4.35 (t, J=8 Hz, 4H), 2.74 (s, br, 1H), 2.53 (p, J=7 Hz,2H).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidine-3-carboxylic acid(˜600 mg, 2 mmol) was dissolved in MeOH (100 mL) and H₂SO₄ (2 drops)were added. A reflux condenser was fitted and the reaction gentlyrefluxed for 24 h. At this time the reaction was diluted with EtOAc (200mL) and extracted with water (3×100 mL). The crude material was fused toSiO₂ and purified by flash column chromatography (DCM) to giveessentially a quantitative yield (2.08 mmol). The ester (650 mg, 2.08mmol) was dissolved in THF (20 mL) and cooled to 0° C. To this was addedMeMgBr (6 mL, 6 mmol). After 30 min at low temperature the reaction wasbrought to RT and followed by TLC. When the reaction was deemed completethe mixture was cooled back to 0° C. and cautiously quenched withaqueous NH₄Cl. The mixture was then extracted into EtOAc (3×100 mL),dried with MgSO₄ and concentrated in vacuo. The crude material was fusedto SiO₂ and purified by flash column chromatography (20% Acetone in Hex)to give 474 mg of2-(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)propan-2-ol(73% yield). ¹H NMR (500 MHz, CDCl₃) δ=7.20 (s, 1H), 5.89 (s, 1H), 4.26(m, 4H), 2.87 (m, 1H), 1.38 (s, 1H), 1.26 (s, 6H). To a stirringsolution of the tertiary alcohol (223 mg, 0.71 mmol) dissolved in THF(10 mL) and cooled to 0° C. was added NaH (600 mg, 20 mmol). Once theinitial bubbling had subsided MeI (1.14 g, 8 mmol) was added dropwiseand the reaction mixture was left to come to RT. After 18 h the reactionwas cooled back to 0° C. and NH₄Cl was cautiously added. The reactionmixture was extracted with EtOAc (3×50 mL), washed with brine, (1×50 mL)and concentrated in vacuo. The crude material was then purified by flashcolumn chromatography (10% Acetone in Hex). To a solution of the ether(193 mg, 0.6 mmol) in DME (4 mL)/Na₂CO₃ (2M, 0.9 mL) was added3-formyl-phenylboronic acid (133 mg, 0.9 mmol) and Pd(P(Ph)₃)₄ (40 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 110° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudealdehyde was purified by plugging through SiO₂ (20% EtOAc in Hex) togive 184 mg of material which was used as is. To a stirring solution ofaldehyde (400 mg, 1.4 mmol) and Rupert's reagent (483 mg, 3.3 mmol) inDCM (13 mL) at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.2 mmol). After30 min at low temperature the cold bath was removed and the reaction wasallowed to come to RT. After stirring overnight an excess of TBAF wasadded and the reaction was diluted with DCM. The organic phases werewashed with saturated NH₄Cl, brine, and then dried with MgSO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (30% EtOAc in Hex) to give 90 mg (41% yield). ¹H NMR (500MHz, CDCl₃) δ=7.72 (s, 1H), 7.66 (m, 1H), 7.50 (m, 2H), 7.11 (s, 1H),6.01 (s, 1H), 5.11 (m, 1H), 4.25 (m, 4H), 3.24 (s, 3H), 2.96 (m, 1H)

To a stirring solution of(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)methanol (427 mg,1.58 mmol) dissolved in NMP (10 mL) and cooled to 0° C. was added NaH(758 mg, 20 mmol). Once the initial bubbling had subsided MeI (2.24 g,10 mmol) was added dropwise and the reaction mixture was left to come toRT. After 18 h the reaction was cooled back to 0° C. and NH₄Cl wascautiously added. The reaction mixture was extracted with EtOAc (3×50mL), washed with brine, (1×50 mL) and concentrated in vacuo. The crudematerial was then purified by flash column chromatography (10% EtOAc inHex). ¹H NMR (500 MHz, CDCl₃) δ=7.16 (s, 1H), 5.86 (s, 1H), 4.3 (m, 2H),4.09 (m, 2H), 3.6 (d, J=6 Hz 2H), 3.40 (s, 3H), 3.08 (m, 1H). To asolution of the methyl ether (245 mg, 0.8 mmol) in DME (5 mL)/Na₂CO₃(2M, 1.2.0 mL) was added 3-formyl-phenylboronic acid (184 mg, 1.9 mmol)and Pd(P(Ph)₃)₄ (40 mg). The flask was then fitted with a refluxcondenser, purged with argon and heated to 110° C. O/N. The reaction wasworked up by pouring into 1 M NaOH (150 mL) and vacuum isolating theresultant solids. The crude material was purified by plugging throughSiO₂ (DCM) to give 214 mg of aldehyde which was used as is. ¹H NMR (500MHz, CDCl₃) δ=10.11 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.88(d, J=8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.17 (s, 1H), 6.03 (s, 1H), 4.42(m, 2H), 4.13 (m, 2H), 3.65 (d, J=6 Hz, 2H), 3.41 (s, 3H), 3.11 (m, 1H).To a stirring solution of the aldehyde (214 mg, 1.33 mmol) and Rupert'sreagent (298 mg, 2.1 mmol) in DCM (13 mL) at 0° C. was added TBAF (0.2mL, 1 M THF, 0.2 mmol). After 30 min at low temperature the cold bathwas removed and the reaction was allowed to come to RT. After 3 hours anexcess of TBAF was added and the reaction was diluted with DCM. Theorganic phases were washed with saturated NH₄Cl, brine, and then driedwith MgSO₄ and concentrated in vacuo. The crude material was purified byflash column chromatography (30% EtOAc in Hex) to give 150 mg (94%yield). ¹H NMR (500 MHz, CDCl₃) δ=7.71 (m, 1H), 7.64 (m, 1H), 7.51 (m,2H), 7.13 (s, 1H), 6.02 (s, 1H), 5.11 (m 1H), 4.38 (t, J=8 Hz, 2H), 4.11(m, 2H), 3.64 (d, J=7 Hz, 2H), 3.41 (s, 3H), 3.09 (m, 1H).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidine-3-carboxylic acid (250mg, 0.8 mmol) in DME (5 mL)/Na₂CO₃ (2M, 1.2 mL) was added3-formyl-phenylboronic acid (181 mg, 1.2 mmol) and Pd(P(Ph)₃)₄ (50 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 110° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudealdehyde was purified by plugging through SiO₂ (30% EtOAc in Hex) togive 211 mg of material which was used as is. To a stirring solution ofaldehyde (211 mg, 0.63 mmol) and Rupert's reagent (266 mg, 1.88 mmol) inDCM (10 mL) at 0° C. was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After30 min at low temperature the cold bath was removed and the reaction wasallowed to come to RT. After 3 hours an excess of TBAF was added and thereaction was diluted with DCM. The organic phases were washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(20-40% EtOAc gradient in Hex) to give 70 mg (27% yield). ¹H NMR (500MHz, CDCl₃) δ=7.71 (s, 1H), 7.64 (m, 1H), 7.49 (m, 2H), 7.13 (s, 1H),6.04 (s, 1H), 5.12 (s, br, 1H), 4.33 (t, J=8 Hz, 2H), 4.25 (m, 2H), 2.91(m, 1H), 2.74 (d, J=4 Hz, 1H), 1.43 (s, 1H), 1.27 (s, 6H).

To a stirring solution of1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (280 mg, 1.04mmol) dissolved in DCM (10 mL) was added Dess-Martin reagent (571 mg,1.3 mmol) dissolved in DCM (4 mL). After 1 hour the reaction had becometurbid and a precipitate had formed. The material was poured in to 1 MNaOH and extracted with TBME, the resultant ketone was used as is. ¹HNMR (500 MHz, CDCl₃) δ=7.40 (s, 1H), 6.13 (s, 1H), 5.10 (s, 4H). To acooled 0° C. stirring solution of ketone (275 mg, 1.03 mmol) dissolvedin THF (10 mL) was added MeMgBr (1M THF, 3 mL). The cold bath was leftin place and the reaction was allowed to come to RT over 8 hours. Atthis time the mixture was re-cooled and quenched with NH₄Cl_((aq)) andextracted with EtOAc (3×20 mL), dried with MgSO₄ and concentrated invacuo. The crude tertiary alcohol was passed through a plug of SiO₂(DCM) to give a yellow solid. To a solution of tertiary alcohol (284 mg,1 mmol) in DME (6 mL)/Na₂CO₃ (2M, 1.5 mL) was added3-formyl-phenylboronic acid (225 mg, 1.5 mmol) and Pd(P(Ph)₃)₄ (40 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 110° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by plugging through SiO₂ (10-30% gradient EtOAc inHex) to give 250 mg of aldehyde which was used as is. ¹H NMR (500 MHz,CDCl₃) δ=10.11 (s, 1H), 8.11 (s, 1H), 7.92 (d, J=8 Hz, 1H), 7.87 (d, J=8Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.21 (s, 1H), 6.09 (s, 1H), 4.30 (d, J=9Hz, 2H), 4.24 (d, J=8 Hz, 2H), 2.19 (s, Br, 1H), 1.71 (s, 3H). To astirring solution of aldehyde (250 mg, 0.81 mmol) and Rupert's reagent(344 mg, 2.4 mmol) in DCM (10 mL) at 0° C. was added TBAF (0.2 mL, 1 MTHF, 0.2 mmol). After 30 min at low temperature the cold bath wasremoved and the reaction was allowed to come to RT. After 3 hours anexcess of TBAF was added and the reaction was diluted with DCM. Theorganic phases were washed with saturated NH₄Cl, brine, and then driedwith MgSO₄ and concentrated in vacuo. The crude material was purified byflash column chromatography (20-40% EtOAc gradient in Hex) to give 185mg (60% yield). ¹H NMR (500 MHz, CDCl₃) δ=7.71 (s, 1H), 7.64 (d, J=7 Hz,1H), 7.51 (m, 2H), 7.18 (s, 1H), 6.08 (s, 1H), 5.12 (m, 1H), 4.29 (d,J=9 Hz, 2H), 4.22 (d, J=9 Hz, 2H), 2.71 (s, br, 1H). 2.10 (s, br, 1H),1.70 (s, 3H).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (0.500 g, 1.85mmol) was dissolved in NMP (2 mL) and cooled to 0° C. NaH (0.096 g, 2.4mmol) was then added portionwise and stirring was continued until allbubbling ceased, at which point ethyl iodide (0.16 mL, 2.0 mmol) wasadded. The reaction was allowed to warm to room temperature overnight.The mixture was then re-cooled to 0° C. and quenched with saturatedNH₄Cl (aq). This mixture was then extracted with EtOAc. The combinedorganic layers were washed with water (2×) brine, dried (Na₂SO₄),filtered and concentrated to give a crude ethyl ether. This ether and3-formylphenylboronic acid (0.2908 g, 1.94 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (4.1 mL)and 2M Na₂CO₃ (2.8 mL, 5.6 mmol) were then added followed by Pd(PPh₃)₄(0.1075 g, 0.093 mmol). The tube was then sealed and heated to 100° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil was then dissolved in THF (5.6 mL) andcooled to 0° C. CF₃TMS (0.41 mL, 2.8 mmol) was added followed by TBAF(0.1 mL, 1.0 M solution in THF). The reaction was then stirred for 60minutes before re-cooling to 0° C. TBAF (5.6 mL, 1.0 M solution in THF)was added and the reaction was allowed to warm to room temperatureovernight. The mixture was quenched with brine and then extracted withEtOAc. The combined organic layers were washed with water (2×), brine,dried (Na₂SO₄), filtered and concentrated to give a crude oil. Thismaterial was purified via flash column chromatography (20% EtOAc/hexane)to afford 0.3755 g (51% yield over 3 steps) of TRV-1437. ¹H NMR (CDCl3,500 MHz) δ=7.72 (s, 1H), 7.66-7.64 (m, 1H), 7.55-7.50 (m, 2H), 7.17 (s,1H), 6.06 (s, 1H), 5.14-5.11 (m, 1H), 4.56-4.54 (m, 3H), 4.18 (d, J=5Hz, 2H), 3.54 (q, J=5 Hz, 2H), 2.67 (d, J=5 Hz, 1H), 1.26 (t, J=5 Hz,3H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(2.085 g, 6.20 mmol) was added to a tube, which was then evacuated andpurged with argon (3 cycles). To this vial was then addeddiethylmalonate (1.9 mL, 12.4 mmol), P(tBu)₃ (4 mL, 1.98 mmol) andtoluene (18 mL) before adding Pd₂(dba)₃ (0.4542 g, 0.496 mmol) and K₃PO₄(4.6063 g, 21.7 mmol). The tube was then sealed and heated to 100° C.for 16 hours. The reaction was then cooled and filtered through a plugof Celite and then concentrated. The residue was purified via flashchromatography (15% EtOAc/hexane) to afford 1.257 g (49% yield) ofsubstituted malonate. This material (1.2572 g, 3.03 mmol) was dissolvedin DMSO (30 mL) and NaCl (0.3536 g, 6.05 mmol) and H₂O (1.8 mL, 97 mmol)were then added. This mixture was heated to 150° C. for 8 hours. Uponcooling to room temperature the mixture was diluted with EtOAc andwater. The organic layer was then washed with H₂O (6×), brine, dried(Na₂SO₄), filtered and concentrated to give the crude ethyl ester. Thismaterial was purified via flash chromatography (10% EtOAc/hexane) toafford 0.7641 g (73% yield) of orange solid. The ethyl ester (0.5873 g,1.71 mmol) was then dissolved in DCM (20 mL) and cooled to −78° C. DIBAL(4.0 mL, 1.0 M solution in hexane) was added dropwise. The reaction wasstirred at −78° C. for 5 minutes and then warmed to −30° C. Afterstirring at this temperature for 3 hours it was quenched with methanoland allowed to warm to room temperature. Water (5 mL) and Na₂SO₄ wereadded, the mixture was stirred for 30 minutes and then filtered to givea mixture of the aldehyde and alcohol. This mixture was taken up in DCM(50 mL) and then DMP (0.7253 g, 1.71 mmol) were added with vigorousstirring. After 60 minutes the reaction was quenched with saturatedaqueous NaHCO₃ and excess Na₂S₂O₃, stirring was continued until all thesolids dissolved. The mixture was then extracted with DCM. The combinedorganic layers were dried with Na₂SO₄, filtered and concentrated. Theresidue was then purified via flash chromatography (20% EtOAc/hexane) toafford 0.0726 g (14% yield, 2 steps) of aldehyde 9. This aldehyde(0.0726 g, 0.243 mmol) was dissolved in THF (5 mL) and cooled to 0° C.CF₃TMS (0.05 mL) was added followed by TBAF (0.03 mL, 1.0 M solution inTHF). The mixture was stirred for 60 minutes and then TBAF (0.46 mL, 1.0M solution in THF) was added and the reaction was stirred overnight. Thereaction was then quenched with brine and extracted with EtOAc. Thecombined organic layers were washed with water (2×), brine, dried(Na₂SO₄), filtered and concentrated to give a crude oil. This materialwas purified via flash column chromatography (20% EtOAc/hexane) toafford 0.0349 g (39% yield) of TRV-1438. ¹H NMR (CDCl3, 500 MHz)δ=7.23-7.21 (m, 2H), 7.03-6.99 (m, 3H), 6.01 (s, 1H), 5.08 (s, 2H), 4.23(br s, 1H), 3.11 (s, 3H), 3.03 (dd, J=14, 2.5 Hz, 1H), 2.87 (dd, J=14,10 Hz, 1H), 2.21 (s, 1H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(2.085 g, 6.20 mmol) was added to a tube, which was then evacuated andpurged with argon (3 cycles). To this vial was then addeddiethylmalonate (1.9 mL, 12.4 mmol), P(tBu)₃ (4 mL, 1.98 mmol) andtoluene (18 mL) before adding Pd₂(dba)₃ (0.4542 g, 0.496 mmol) and K₃PO₄(4.6063 g, 21.7 mmol). The tube was then sealed and heated to 100° C.for 16 hours. The reaction was then cooled and filtered through a plugof Celite and then concentrated. The residue was purified via flashchromatography (15% EtOAc/hexane) to afford 1.257 g (49% yield) ofcompound 2. This material (1.2572 g, 3.03 mmol) was dissolved in DMSO(30 mL) and NaCl (0.3536 g, 6.05 mmol) and H₂O (1.8 mL, 97 mmol) werethen added. This mixture was heated to 150° C. for 8 hours. Upon coolingto room temperature the mixture was diluted with EtOAc and water. Theorganic layer was then washed with H₂O (6×), brine, dried (Na₂SO₄),filtered and concentrated to give the crude ethyl ester. This materialwas purified via flash chromatography (10% EtOAc/hexane) to afford0.7641 g (73% yield) of orange solid. This material (0.1736 g, 0.506mmol) was dissolved in THF (10 mL) and cooled to −78° C. MeLi (0.70 mL,1.6 M solution in Et₂O) was added dropwise, and the reaction was allowedto slowly warm to room temperature. It was then re-cooled to 0° C. andquenched with ammonium chloride. This mixture was extracted with EtOAcand the combined organic extracts were washed with H₂O (3×), brine,dried (Na₂SO₄), filtered and concentrated to give a crude residue. Thecrude material was purified via flash chromatography (20% EtOAc/hexane)to afford 0.0288 g (17% yield) of the tertiary alcohol TRV-1439. ¹H NMR(CDCl3, 500 MHz) δ=7.24-7.21 (m, 2H), 7.05-6.99 (m, 2H), 6.94 (s, 1H),6.08 (s, 1H), 5.02 (s, 2H), 3.11 (s, 3H), 2.76 (s, 2H), 1.40 (s, 1H),1.27 (s, 6H).

To a solution of 4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole (480mg, 0.6 mmol) in DME (11 mL)/Na₂CO₃ (2M, 2.8 mL) was added3-carboxy-phenylboronic acid (470 mg, 2.8 mmol) and Pd(P(Ph)₃)₄ (93 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 100° C. O/N. The reaction was worked up by pouring into 1 MHCl (150 mL) and vacuum isolating the resultant solids. The crude acidwas purified by flash column chromatography (DCM 1% AcOH) to give 330 mgof material which was used as is. To a stirring solution of this acid(110 mg, 0.37 mmol) dissolved in NMP (2 mL) was added DIPEA (130 μL,0.74 mmol) and piperazine (230 mg, 0.37 mmol). After the mixture washomogeneous HATU (140 mg, 0.37 mmol) was added and the reaction was leftto stir. After 1 hour at RT the reaction was diluted with EtOAc (100 mL)and diluted with water. The crude material was purified by flash columnchromatography (50-100% EtOAc in Hex) to give (20 mg) 14% yield. ¹H NMR(500 MHz, CDCl₃) δ=7.66 (m, 2H), 7.50 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz,1H), 7.12 (s, 1H), 6.01 (s, 1H), 4.34 (t, J=7 Hz, 4H), 3.79 (s, broad,2H), 3.43 (s, broad, 2H), 2.97 (s, broad, 2H), 2.82 (s, broad, 2H), 2.61(s, 1H), 2.53 (p, J=7 Hz, 2H).

To a solution of 4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole (480mg, 0.6 mmol) in DME (11 mL)/Na₂CO₃ (2M, 2.8 mL) was added3-carboxy-phenylboronic acid (470 mg, 2.8 mmol) and Pd(P(Ph)₃)₄ (93 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 100° C. O/N. The reaction was worked up by pouring into 1 MHCl (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by flash column chromatography (DCM 1% AcOH) togive 330 mg of material which was used as is. To a stirring solution ofthis acid (165 mg, 0.56 mmol) dissolved in NMP (2 mL) was added DIPEA(300 μL, 1.7 mmol) and cyclopropylamine (55 mg, 0.59 mmol). After themixture was homogeneous HATU (213 mg, 0.56 mmol) was added and thereaction was left to stir. After 1 hour at RT the reaction was dilutedwith EtOAc (100 mL) and diluted with water. The organic phase was washedwith acid (1 M HCl, 1×100 mL), base (1M NaOH, 1×100 mL) and concentratedin vacuo. The crude material was purified by flash column chromatography(EtOAc) to give (120 mg) 64% yield. ¹H NMR (500 MHz, DMSO-D₆) δ=7.91 (m,2H), 7.66 (d, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 1H), 7.35 (s, 1H), 6.23 (s,1H), 4.33 (m, 6H), 4.07 (t, J=7 Hz, 2H), 2.45 (p, J=7 Hz, 2H), 2.27 (p,J=7 Hz, 2H).

To a solution of 4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole (480mg, 0.6 mmol) in DME (11 mL)/Na₂CO₃ (2M, 2.8 mL) was added3-carboxy-phenylboronic acid (470 mg, 2.8 mmol) and Pd(P(Ph)₃)₄ (93 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 100° C. O/N. The reaction was worked up by pouring into 1 MHCl (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by flash column chromatography (DCM 1% AcOH) togive 330 mg of material which was used as is. To a stirring solution ofthis acid (110 mg, 0.37 mmol) dissolved in NMP (2 mL) was added DIPEA(130 μL, 0.74 mmol) and morpholine (32 μL, 0.37 mmol). After the mixturewas homogeneous HATU (140 mg, 0.37 mmol) was added and the reaction wasleft to stir. After 1 hour at RT the reaction was diluted with EtOAc(100 mL) and diluted with water. The organic phase was washed with acid(1 M HCl, 1×100 mL), base (1M NaOH, 1×100 mL) and concentrated in vacuo.The crude material was purified by flash column chromatography (50-100%EtOAc in Hex) to give (40 mg) 29% yield. ¹H NMR (500 MHz, CDCl₃) δ=7.67(m, 2H), 7.52 (t, J=8 Hz, 1H), 7.43 (d, J=7 Hz, 1H), 7.12 (s, 1H), 6.00(s, 1H), 4.35 (t, J=7 Hz, 4H), 3.81 (m, br, 4H), 3.65 (m, br, 2H), 3.49(m, br, 2H), 2.54 (p, J=7 Hz, 2H).

To a solution of 4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole (480mg, 0.6 mmol) in DME (11 mL)/Na₂CO₃ (2M, 2.8 mL) was added3-carboxy-phenylboronic acid (470 mg, 2.8 mmol) and Pd(P(Ph)₃)₄ (93 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 100° C. O/N. The reaction was worked up by pouring into 1 MHCl (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by flash column chromatography (DCM 1% AcOH) togive 330 mg of material which was used as is. To a stirring solution ofthis acid (165 mg, 0.56 mmol) dissolved in NMP (2 mL) was added DIPEA(300 μL, 1.7 mmol) and azetidine hydrochloride (55 mg, 0.59 mmol). Afterthe mixture was homogeneous HATU (213 mg, 0.56 mmol) was added and thereaction was left to stir. After 1 hour at RT the reaction was dilutedwith EtOAc (100 mL) and diluted with water. The organic phase was washedwith acid (1 M HCl, 1×100 mL), base (1M NaOH, 1×100 mL) and concentratedin vacuo. The crude material was purified by flash column chromatography(EtOAc) to give (120 mg) 64% yield. ¹H NMR (500 MHz, DMSO-D₆) δ=7.91 (m,2H), 7.66 (d, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 1H), 7.35 (s, 1H), 6.23 (s,1H), 4.33 (m, 6H), 4.07 (t, J=7 Hz, 2H), 2.45 (p, J=7 Hz, 2H), 2.27 (p,J=7 Hz, 2H).

To a solution of 4-(azetidin-1-yl)-6-bromobenzo[c][1,2,5]oxadiazole (480mg, 0.6 mmol) in DME (11 mL)/Na₂CO₃ (2M, 2.8 mL) was added3-carboxy-phenylboronic acid (470 mg, 2.8 mmol) and Pd(P(Ph)₃)₄ (93 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 100° C. O/N. The reaction was worked up by pouring into 1 MHCl (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by flash column chromatography (DCM 1% AcOH) togive 330 mg of material which was used as is. To a stirring solution ofthis acid (165 mg, 0.56 mmol) dissolved in NMP (2 mL) was added DIPEA(300 μL, 1.7 mmol) and 3-hydroxyazetidine hydrochloride (64 mg, 0.59mmol). After the mixture was homogeneous HATU (212 mg, 0.56 mmol) wasadded and the reaction was left to stir. After 1 hour at RT the reactionwas diluted with EtOAc (100 mL) and diluted with water. The organicphase was washed with acid (1 M HCl, 1×100 mL), base (1M NaOH, 1×100 mL)and concentrated in vacuo. The crude material was purified by flashcolumn chromatography (EtOAc) to give (60 mg) 30% yield. ¹H NMR (500MHz, DMSO-D₆) δ=7.89 (m, 2H), 7.67 (d, J=8 Hz, 1H), 7.58 (t, J=8 Hz,1H), 7.35 (s, 1H), 6.22 (s, 1H), 4.50 (m 2H), 4.29 (m, 5H), 4.08 (m,1H), 3.80 (dd, J=10 Hz, 2 Hz, 1H), 2.45 (p, J=7 Hz, 2H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.3010 g, 0.895 mmol) and 3-acetylphenylboronic acid (0.1542 g, 0.940mmol) were massed into a tube. The tube was evacuated and purged withargon (3×). DME (2.1 mL) and 2M Na₂CO₃ (1.4 mL, 2.69 mmol) were thenadded followed by Pd(PPh₃)₄ (0.0518 g, 0.0448 mmol). The tube was thensealed and heated to 100° C. overnight. Upon cooling to room temperaturethe mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc. The combinedorganic layers were then washed with water (5×), brine, dried (Na₂SO₄),filtered and concentrated to give an oil. This crude oil was thendissolved in THF (10 mL) and cooled to 0° C. MeMgBr (1.2 mL, 1.0 Msolution in Bu₂O) was added dropwise and then the reaction was allowedto slowly warm to room temperature overnight. The reaction was cooled to0° C. and quenched with saturated ammonium chloride. This mixture wasthen extracted with EtOAc. The combined organic layers were washed withwater (3×), brine, dried (Na₂SO₄), filtered and concentrated. The oilwas purified via flash chromatography (20% EtOAc/hexane) to afford0.0841 g (24% yield, 2 steps) of TRV-1445. ¹H NMR (CDCl3, 500 MHz)δ=7.75 (d, J=5 Hz, 1H), 7.54 (d, J=10 Hz, 1H), 7.49-7.43 (m, 2H),7.25-7.24 (m, 3H), 7.02 (t, J=7 Hz, 2H), 6.38 (s, 1H), 5.11 (s, 2H),3.18 (s, 3H), 1.78 (s, 1H), 1.64 (s, 6H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(0.3207 g, 0.954 mmol) and 3-bromophenylboronic acid (0.164 g, 1.00mmol) were massed into a tube. The tube was evacuated and purged withargon (3×). DME (2.1 mL) and 2M Na₂CO₃ (1.4 mL, 2.86 mmol) were thenadded followed by Pd(PPh₃)₄ (0.0551 g, 0.0477 mmol). The tube was thensealed and heated to 100° C. overnight. Upon cooling to room temperaturethe mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc. The combinedorganic layers were then washed with water (5×), brine, dried (Na₂SO₄),filtered and concentrated to give an oil. The crude oil was purified viaflash chromatography (5% EtOAc/hexane) to afford 0.3037 g (77% yield) ofthe corresponding aryl bromide. This aryl bromide (0.3037 g, 0.74 mmol)was dissolved in THF (7.5 mL) and cooled to −78° C. nBuLi (0.39 mL, 2.0M solution in cyclohexane) was added drop wise. The solution was stirredfor 30 minutes at this temperature and then oxetan-3-one (0.0692 g,0.962 mmol) in THF (1 mL) was added drop wise. The solution was thenstirred and allowed to warm to room temperature overnight. The reactionwas cooled to 0° C. and quenched with saturated ammonium chloride. Thismixture was extracted with EtOAc. The combined organic layers werewashed with water (3×), brine, dried (Na₂SO₄), filtered and concentratedto a crude oil. The oil was then purified via flash chromatography (45%EtOAc/hexane) to afford 0.0587 g (19% yield) of TRV-1446. ¹H NMR (CDCl3,500 MHz) δ=7.83 (s, 1H), 7.70 (d, J=5 Hz, 1H), 7.58 (d, J=5 Hz, 1H),7.53 (t, J=10 Hz, 1H), 7.25-7.24 (m, 3H), 7.02 (t, J=10 Hz, 2H), 6.36(s, 1H), 5.12 (s, 2H), 4.96 (s, 4H), 3.18 (s, 3H), 2.62 (s, 1H).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (0.500 g, 1.85mmol) was dissolved in NMP (2 mL) and cooled to 0° C. NaH (0.096 g, 2.4mmol) was then added portion wise and stirring was continued until allbubbling ceased, at which point 2-bromopropane (0.19 mL, 2.0 mmol) wasadded. The reaction was allowed to warm to room temperature overnight.The mixture was then re-cooled to 0° C. and NaH (0.192 g, 4.8 mmol),2-bromopropane (1.8 mL, 19 mmol) and NaI (1 eq) were added. The reactionwas heated to 50° C. overnight. The mixture was then re-cooled to 0° C.and quenched with saturated NH₄Cl (aq). This mixture was then extractedwith EtOAc. The combined organic layers were washed with water (2×)brine, dried (Na₂SO₄), filtered and concentrated to give the crudeisopropyl ether. This ether (0.1942 g, 0.622 mmol) and3-formylphenylboronic acid (0.0979 g, 1.94 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (1.4 mL)and 2M Na₂CO₃ (0.93 mL, 1.87 mmol) were then added followed by Pd(PPh₃)₄(0.0359 g, 0.0311 mmol). The tube was then sealed and heated to 100° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil (0.1047 g, 0.31 mmol) was then dissolved inTHF (1.0 mL) and cooled to 0° C. CF₃TMS (0.092 mL, 0.62 mmol) was addedfollowed by TBAF (0.03 mL, 1.0 M solution in THF). The reaction was thenstirred for 60 minutes before re-cooling to 0° C. TBAF (1.0 mL, 1.0 Msolution in THF) was added and the reaction was allowed to warm to roomtemperature overnight. The mixture was quenched with brine and thenextracted with EtOAc. The combined organic layers were washed with water(2×), brine, dried (Na₂SO₄), filtered and concentrated to give a crudeoil. This material was purified via flash column chromatography (20%EtOAc/hexane) to afford 0.073 g (58% yield over 3 steps) of TRV-1447. ¹HNMR (CDCl3, 500 MHz) δ=7.71 (s, 1H), 7.65 (d, J=5 Hz, 1H), 7.54-7.50 (m,2H), 7.16 (s, 1H), 6.06 (s, 1H), 5.13-5.12 (m, 1H), 4.60-4.55 (m, 3H),4.16-4.14 (m, 2H), 3.70 (sept, J=5 Hz, 1H), 2.71 (s, 1H), 1.21 (d, J=5Hz, 6H).

To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (396 mg, 1.7mmol) in NMP (3 mL) in a 4 dram vial was added 3-hydroxypyrrolidinehydrochloride (230 mg, 1.83 mmol) and triethylamine (710 μL, 5.1 mmol).A cap was tightly fitted and the reaction was heated at 85° C. O/N.Reaction worked up by diluting with EtOAc (60 mL) and washing with 1MHCl (3×20 mL) and brine (1×20 mL). The organic phase was dried withMgSO₄ filtered and concentrated in vacuo. The crude aniline was usedwithout further purification. To a solution of aniline (820 mg, 2.9mmol) in DME (12 mL)/Na₂CO₃ (2M, 4.4 mL) was added3-formyl-phenylboronic acid (645 mg, 4.3 mmol) and Pd(P(Ph)₃)₄ (110 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 110° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by plugging through SiO₂ (EtOAc) to give 680 mg ofmaterial which was used as is. ¹H NMR (500 MHz, CDCl₃) δ=10.11 (s, 1H),8.12 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.88 (d, J=8 Hz, 1H), 7.65 (t, J=8Hz, 1H), 7.17 (s, 1H), 6.03 (s, 1H), 4.42 (m, 2H), 4.13 (m, 2H), 3.65(d, J=6 Hz, 2H), 3.41 (s, 3H), 3.11 (m, 1H). To a stirring solution ofthe aldehyde (680 mg, 2.2 mmol) and Rupert's reagent (937 mg, 6.6 mmol)in DCM (20 mL) at 0° C. was added TBAF (0.2 mL, 1 M THF, 0.2 mmol).After 30 min at low temperature the cold bath was removed and thereaction was allowed to come to RT. After 3 hours the reaction wasconcentrated in vacuo and the flask was charged with THF (20 mL). Tothis an excess of TBAF was added and the reaction was left to stir. Oncethe deprotection was complete EtOAc (100 mL) was added and the reactionwas washed with saturated NH₄Cl, brine, and then dried with MgSO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (50% EtOAc in Hex) to give 380 mg (38% yield) ofTRV-1448, a 1:1:1:1 mixture of diastereomers due to the two chiralcenters. ¹H NMR (500 MHz, CDCl₃) δ=7.73 (s, 1H), 7.66 (dt J=7 Hz, 2 Hz,2H), 7.51 (m, 2H), 7.10 (s, 1H), 6.12 (s, 1H), 5.1 (m, 1H), 4.7 (s br,1H), 3.96 (m, 4H), 2.81 (d, J=3 Hz, 1H), 2.20 (m, 2H), 1.75 (d, J=3 Hz,1H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3765 g, 1.35 mmol), ethylpyrrolidine-2-carboxylate hydro chloride (0.2677 g, 1.49 mmol) and DIPEA(0.59 mL, 3.38 mmol) were dissolved in NMP (1.8 mL) under argon andstirred in a sealed tube at 100° C. overnight. Upon cooling to roomtemperature, the reaction was diluted with water and extracted withEtOAc. The combined organic layers were washed with H₂O (5×), 1 N HCl(aq), saturated NaHCO₃ (aq) and brine before drying with Na₂SO₄,filtering and concentrating to give 0.1756 g (38% yield) of crudematerial. The aniline (0.4346 g, 1.28 mmol) was then dissolved in THF(12 mL) and cooled to 0° C. MeMgBr (3.2 mL, 1.0 M solution in Bu₂O) wasadded dropwise and the reaction was slowly allowed to warm to roomtemperature overnight. The reaction was quenched with NH₄Cl (aq) andthen extracted with EtOAc. The combined organic layers were then washedwith water (3×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. The oil was then purified via flash chromatography (15%EtOAc/hexane) to afford 0.1293 g (31% yield) of tertiary alcohol. Thetertiary alcohol (0.1293 g, 0.316 mmol) and 3-formylphenylboronic acid(0.0624 g, 0.416 mmol) were massed into a tube. The tube was evacuatedand purged with argon (3×). DME (1.0 mL) and 2M Na₂CO₃ (0.6 mL, 1.19mmol) were then added followed by Pd(PPh₃)₄ (0.0229 g, 0.0198 mmol). Thetube was then sealed and heated to 100° C. overnight. Upon cooling toroom temperature the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was back-extracted withEtOAc. The combined organic layers were then washed with water (5×),brine, dried (Na₂SO₄), filtered and concentrated to give an oil. Thiscrude oil was then dissolved in THF (3 mL) and cooled to 0° C. CF₃TMS(0.12 mL, 0.792 mmol) was added followed by TBAF (0.05 mL, 1.0 Msolution in THF). The reaction was then stirred for 60 minutes beforere-cooling to 0° C. TBAF (1.4 mL, 1.0 M solution in THF) was added andthe reaction was allowed to warm to room temperature overnight. Themixture was quenched with brine and then extracted with EtOAc. Thecombined organic layers were washed with water (2×), brine, dried(Na₂SO₄), filtered and concentrated to give a crude oil. This materialwas purified via flash column chromatography (30% EtOAc/hexane) toafford 0.0748 g (45% yield over 2 steps) of TRV-1449. ¹H NMR (CDCl3, 500MHz) δ=7.73 (s, 1H), 7.67-7.65 (m, 1H), 7.54-7.49 (m, 2H), 7.14 (s, 1H),6.46 (s, 1H), 5.12-5.10 (m, 1H), 4.92 (d, J=5 Hz, 1H), 3.99-3.95 (m,1H), 3.73-3.68 (m, 1H), 2.83 (s, 1H), 2.77-2.21 (m, 1H), 2.11-2.02 (m,3H), 1.82 (s, 1H), 1.31 (s, 3H), 1.24 (s, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (2.013 g, 7.24 mmol) and (S)-ethylpyrrolidine-2-carboxylate hydrochloride salt (1.43 g, 7.96 mmol) weremassed into a tube. The tube was evacuated and flushed with argon forthree cycles. NMP (10 mL) and DIPEA (3.5 mL, 19.9 mmol) were then addedand the tube was sealed and heated to 50° C. overnight. Upon cooling toroom temperature the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was back-extracted withEtOAc. The combined organic layers were then washed with water (5×),brine, dried (Na₂SO₄), filtered and concentrated to give an oil. Thecrude oil was then purified via flash column chromatography (15%EtOAc/hexane) to afford 0.6105 g (25% yield) of aniline. The aniline(1.696 g, 4.9 mmol) was dissolved in DCM (20 mL) and cooled to −78° C.DIBAL (12.5 mL, 1.0 M solution in hexanes) was added dropwise and thenthe reaction was allowed to warm to room temperature overnight. Thereaction was quenched with MeOH and then Na₂SO₄ was added and themixture was stirred for 30 minutes before filtering through Celite. Theorganic phase was diluted with EtOAc and water. The layers wereseparated and the organic layer was washed with H₂O (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified viachromatography (30% EtOAc/hexane) to give 1.294 g (87% yield) of theprimary alcohol. This alcohol (0.2926 g, 0.98 mmol) and3-formylphenylboronic acid (0.1544 g, 1.03 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (2.2 mL)and 2M Na₂CO₃ (1.5 mL, 2.94 mmol) were then added followed by Pd(PPh₃)₄(0.0566 g, 0.049 mmol). The tube was then sealed and heated to 100° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil was then dissolved in THF (10 mL) and cooledto 0° C. CF₃TMS (0.29 mL, 1.96 mmol) was added followed by TBAF (0.1 mL,1.0 M solution in THF). The reaction was then stirred for 60 minutesbefore re-cooling to 0° C. and 4N HCl (aq) was added and stirred for 60minutes. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was basified. The aqueous layer was thenre-extracted with EtOAc. The combined organic layers were was withwater, brine, dried (Na₂SO₄), filtered and concentrated to give a crudeoil. This material was purified via flash column chromatography (35%EtOAc/hexane) to afford 0.2158 g (56% yield, 2 steps) of TRV-1450. ¹HNMR (DMSO, 500 MHz) δ=7.87 (s, 1H), 7.79 (d, J=5 Hz, 1H), 7.57-7.54 (m,2H), 7.21 (s, 1H), 6.96 (d, J=5 Hz, 1H), 6.34 (t, J=5 Hz, 1H), 5.29-5.25(m, 1H), 4.91-4.89 (m, 1H), 4.55 (br s, 1H), 3.82-3.81 (m, 1H),3.58-3.57 (m, 3H), 2.12-2.11 (m, 2H), 2.02-1.97 (m, 2H).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidine-3-carboxylic acid (1.5g, 5 mmol) was dissolved in THF (50 mL) and cooled to 0° C. To this wasadded BH₃-THF (10 mL, 10 mmol). The reaction was allowed to come to roomtemperature overnight. The next day the reaction was quenched with AcOHand extracted into EtOAc. The organic layer was washed with 1 M NaOHuntil the washings remained litmus blue and then concentrated in vacuo.The crude material was fused to SiO₂ and purified by flash columnchromatography (3:2 Hex:EtOAc) to give 800 mg of primary alcohol (56%yield). ¹H NMR (500 MHz, CDCl₃) δ=7.05 (s, 1H), 6.11 (s, 1H), 5.30 (s,1H), 4.11 (t, J=8 Hz, 2H), 3.85 (m, 4H), 3.00 (m, 1H). To a stirringsolution of the alcohol (500 mg, 1.76 mmol) in DCM (20 mL) was addedDess-Martin periodane (1.1 g, 2.64 mmol) and the solution was left tostir for 1 hour. At this time the reaction was diluted with EtOAc (100mL) and washed with sodium carbonate (sat.). The organic layer was driedwith MgSO₄, and concentrated in vacuo. The crude material was purifiedby plugging through SiO₂ (DCM) to give 420 mg (1.49 mmol, 84% yield) ofaldehyde. ¹H NMR (500 MHz, CDCl₃) δ=9.96 (d, J=2 Hz, 1H), 7.26 (s, 1H),5.96 (s, 1H), 4.47 (m, 4H), 3.7 (m, 1H). To a 0° C. stirring solution ofthis aldehyde (420 mg, 1.5 mmol) in THF (10 mL) was addedmethylmagnesium bromide (1M, 1.8 mL). After 10 min at reducedtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 1 hour the reaction was cooled back to 0° C. andsaturated NH₄Cl was cautiously added. The reaction mixture was thendiluted with EtOAc (100 mL) and the phases were separated. The organicphase was washed with brine, dried with MgSO₄ and concentrated in vacuo.The crude material was fused to SiO₂ (4 g) and gradient flashed (0-2%MeOH in DCM) to give 380 mg (1.27 mmol, 85% yield) of the secondaryalcohol. ¹H NMR (500 MHz, CDCl₃) δ=7.18 (s, 1H), 5.898 (s, 1H),4.36-4.08 (m, 5H), 2.85 (m, 1H), 1.25 (d, 3H). To a solution of thissecondary alcohol (380 mg, 1.28 mmol) in DME (8 mL)/Na₂CO₃ (2M, 1.9 mL)was added 3-formyl-phenylboronic acid (286 mg, 1.9 mmol) and Pd(P(Ph)₃)₄(70 mg). The flask was then fitted with a reflux condenser, purged withargon and heated to 85° C. O/N. The reaction was worked up by pouringinto 1 M NaOH (150 mL) and vacuum isolating the resultant solids. Thecrude material was purified by plugging through SiO₂ (50% EtOAc in Hex)to give 356 mg of material which was used as is. ¹H NMR (500 MHz, CDCl₃)δ=10.1 (s, 1H), 8.11 (s, 1H), 7.63 (d J=7 Hz, 1H), 7.88 (d, J=7 Hz, 1H),7.65 (t, J=7 Hz, 1H), 7.17 (s, 1H), 6.05 (s, 1H), 4.40 (m, 2H), 4.27 (m,1H), 4.15-4.05 (m, 2H), 2.87 (m, 1H), 1.26 (d, J=6 Hz, 3H). To astirring solution of this aldehyde (356 mg, 1.1 mmol) and Rupert'sreagent (488 μL, 3.3 mmol) in THF (3 mL) at 0° C. was added TBAF (0.2mL, 1 M THF, 0.2 mmol). After 30 min at low temperature the cold bathwas removed and the reaction was allowed to come to RT. After 3 hoursthe reaction was concentrated in vacuo and the flask was charged withTHF (20 mL). To this an excess of TBAF was added and the reaction wasleft to stir. Once the deprotection was complete EtOAc (100 mL) wasadded and the reaction was washed with saturated NH₄Cl, brine, and thendried with MgSO₄ and concentrated in vacuo. The crude material waspurified by flash column chromatography (20-40% EtOAc in Hex) to give100 mg (23% yield) of TRV-1451, a 1:1:1:1 mixture of diastereomers dueto the two chiral centers. ¹H NMR (500 MHz, CDCl₃) δ=7.71 (s, 1H), 7.64(m, 1H), 7.51 (m, 2H), 7.14 (s, 1H), 6.04 (s, 1H), 5.11 (m, 1H), 4.39(m, 2H), 4.24 (m, 1H), 4.10 (m, 2H), 2.85 (m, 1H), 2.74 (m, 1H), 1.26(d, J=6 Hz, 3H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (2.013 g, 7.24 mmol) and (S)-ethylpyrrolidine-2-carboxylate hydrochloride salt (1.43 g, 7.96 mmol) weremassed into a tube. The tube was evacuated and flushed with argon forthree cycles. NMP (10 mL) and DIPEA (3.5 mL, 19.9 mmol) were then addedand the tube was sealed and heated to 50° C. overnight. Upon cooling toroom temperature the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was back-extracted withEtOAc. The combined organic layers were then washed with water (5×),brine, dried (Na₂SO₄), filtered and concentrated to give an oil. Thecrude oil was then purified via flash column chromatography (15%EtOAc/hexane) to afford 0.6105 g (25% yield) of aniline. The aniline(1.696 g, 4.9 mmol) was dissolved in DCM (20 mL) and cooled to −78° C.DIBAL (12.5 mL, 1.0 M solution in hexanes) was added dropwise and thenthe reaction was allowed to warm to room temperature overnight. Thereaction was quenched with MeOH and then Na₂SO₄ was added and themixture was stirred for 30 minutes before filtering through Celite. Theorganic phase was diluted with EtOAc and water. The layers wereseparated and the organic layer was washed with H₂O (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified viachromatography (30% EtOAc/hexane) to give 1.294 g (87% yield) of theprimary alcohol. The primary alcohol (0.9956 g, 3.34 mmol) was dissolvedin DCM (100 mL) and DMP (2.1249 g, 5.0 mmol) was added. The reaction wasstirred for 2 hours and then it was quenched with saturated NaHCO₃ (aq)and excess Na₂SO₄ (8.0 g) was added and the mixture was stirred untilall solids dissolved. This mixture was then extracted with DCM and thecombined organic layer was dried (Na₂SO₄), filtered and concentrated.Purification (20% EtOAc/hexane column) afforded 0.6471 g (65% yield) ofthe aldehyde. This aldehyde (0.200 g, 0.675 mmol) and pyrrolidine (0.06mL, 0.743 mmol) were dissolved in DCM (3.1 mL) and then treated withNaBH(OAc)₃ (0.2003 g, 0.945 mmol) and the mixture was stirred for 2hours. The solution was cooled to 0° C. and quenched with 1N NaOH. Thismixture was then extracted with EtOAc. The combined organic layers werewashed with H₂O (3×), brine, dried (Na₂SO₄), filtered and concentratedto give the crude amine. This amine and 3-formylphenylboronic acid(0.1063 g, 0.709 mmol) were massed into a tube. The tube was evacuatedand purged with argon (3×). DME (1.5 mL) and 2M Na₂CO₃ (1.0 mL, 2.0mmol) were then added followed by Pd(PPh₃)₄ (0.0389 g, 0.033 mmol). Thetube was then sealed and heated to 100° C. overnight. Upon cooling toroom temperature the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was back-extracted withEtOAc. The combined organic layers were then washed with water (5×),brine, dried (Na₂SO₄), filtered and concentrated to give an oil. Thiscrude oil was then dissolved in THF (3 mL) and cooled to 0° C. CF₃TMS(0.20 mL, 1.35 mmol) was added followed by TBAF (0.1 mL, 1.0 M solutionin THF). The reaction was then stirred for 60 minutes before re-coolingto 0° C. and 4N HCl (aq) was added and stirred for 60 minutes. Themixture was diluted with water and EtOAc. The layers were separated andthe aqueous layer was basified. The aqueous layer was then re-extractedwith EtOAc. The combined organic layers were was with water, brine,dried (Na₂SO₄), filtered and concentrated to give a crude oil. Thismaterial was purified via flash column chromatography (5% MeOH/DCM) toafford 0.1537 g (51% yield) of TRV-1452. ¹H NMR (CDCl3, 500 MHz)δ=7.76-7.74 (m, 2H), 7.68-7.65 (m, 2H), 7.51-7.47 (m, 4H), 7.08 (s, 1H),7.07 (s, 1H), 6.22 (s, 1H), 6.21 (s, 1H), 5.11-5.05 (m, 2H), 64.65 (brs, 1H), 4.52 (br s, 1H), 3.94-3.89 (m, 2H), 3.65-3.59 (m, 2H), 2.70-2.52(m, 12H), 2.28-2.25 (m, 2H), 2.14-2.05 (m, 6H), 1.81 (br s, 8H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(1.00 g, 2.97 mmol) and 3-carboxyphenylboronic acid (0.5176 g, 3.12mmol) were massed into a tube. The tube was evacuated and purged withargon (3×). DME (8.9 mL) and 2M Na₂CO₃ (6.0 mL, 11.9 mmol) were thenadded followed by Pd(PPh₃)₄ (0.1733 g, 0.15 mmol). The tube was thensealed and heated to 100° C. overnight. Upon cooling to room temperaturethe mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc. The combinedorganic layers were then washed with water (5×), brine, dried (Na₂SO₄),filtered and concentrated to give the crude material. This was purifiedvia 5% MeOH/DCM column to afford 1.0873 g (97% yield, 90% chemicalpurity) of the acid. A mixture of the acid (0.200 g, 0.529 mmol),cyclopropylamine (0.04 mL, 0.529 mmol) and TEA (0.18 mL, 1.32 mmol) werestirred in EtOAc (6 mL) and cooled in an ice bath. The T3P solution(0.4040 g, 50% w/w in EtOAc) was added dropwise. Once the addition wascomplete the reaction was allowed to warm to room temperature. Thereaction was then quenched with water and extracted with EtOAc. Thecombined organic layers were washed with water (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was thenpurified by chromatography (40% EtOAc/hexane) to give 0.1109 g (50%yield) of TRV-1453. ¹H NMR (CDCl3, 500 MHz) δ=8.01 (s, 1H), 7.72 (dd,J=8, 1.6 Hz, 2H), 7.51 (t, J=8 Hz, 1H), 7.26-7.23 (m, 3H), 7.02 (t, J=8Hz, 2H), 6.35 (s, 1H), 6.32 (br s, 1H), 5.13 (s, 2H), 3.17 (s, 3H),2.94-2.92 (m, 1H), 0.92-0.85 (m, 2H), 0.67-0.64 (m, 2H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(1.00 g, 2.97 mmol) and 3-carboxyphenylboronic acid (0.5176 g, 3.12mmol) were massed into a tube. The tube was evacuated and purged withargon (3×). DME (8.9 mL) and 2M Na₂CO₃ (6.0 mL, 11.9 mmol) were thenadded followed by Pd(PPh₃)₄ (0.1733 g, 0.15 mmol). The tube was thensealed and heated to 100° C. overnight. Upon cooling to room temperaturethe mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc. The combinedorganic layers were then washed with water (5×), brine, dried (Na₂SO₄),filtered and concentrated to give the crude material. This was purifiedvia 5% MeOH/DCM column to afford 1.0873 g (97% yield, 90% chemicalpurity) of the acid. A mixture of the acid (0.200 g, 0.529 mmol),morpholine (0.05 mL, 0.529 mmol) and TEA (0.18 mL, 1.32 mmol) werestirred in EtOAc (6 mL) and cooled in an ice bath. The T3P solution(0.4040 g, 50% w/w in EtOAc) was added dropwise. Once the addition wascomplete the reaction was allowed to warm to room temperature. Thereaction was then quenched with water and extracted with EtOAc. Thecombined organic layers were washed with water (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was thenpurified by chromatography (65% EtOAc/hexane) to give 0.1331 g (56%yield) of TRV-1454. ¹H NMR (CDCl3, 500 MHz) δ=7.67 (d, J=10 Hz, 1H),7.64 (s, 1H), 7.52 (t, J=10 Hz, 1H), 7.44-7.41 (m, 2H), 7.26-7.23 (m,2H), 7.02 (t, J=10 Hz, 2H), 6.33 (s, 1H), 5.13 (s, 2H), 3.81 (br s, 4H),3.63 (br s, 2H), 3.48 (br s, 2H), 3.17 (s, 3H).

To a stirring solution of(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)methanol (500 mg,1.76 mmol) in DCM (20 mL) was added Dess-Martin periodane (1.1 g, 2.64mmol) and the solution was left to stir for 1 hour. At this time thereaction was diluted with EtOAc (100 mL) and washed with sodiumcarbonate (sat.). The organic layer was dried with MgSO₄, andconcentrated in vacuo. The crude material was purified by pluggingthrough SiO₂ (DCM) to give 420 mg (1.49 mmol, 84% yield) of aldehyde. ¹HNMR (500 MHz, CDCl₃) δ=9.96 (d, J=2 Hz, 1H), 7.26 (s, 1H), 5.96 (s, 1H),4.47 (m, 4H), 3.7 (m, 1H). To a stirring solution of this aldehyde (316mg, 1.1 mmol) in DCM (5 mL) was added morpholine (105 μL, 1.21 mmol)followed by sodium triacetoxyborohydride (326 mg, 1.54 mmol). When thereaction was deemed complete (monitored by TLC), it was diluted with DCM(100 mL) and washed with water (50 mL), sodium hydroxide (1M, 50 mL),then dried with MgSO₄ and concentrated in vacuo to give 406 mg of amine.The material was used without further purification. ¹H NMR (500 MHz,CDCl₃) δ=7.16 (s, 1H), 5.85 (s, 1H), 4.39 (m 2H), 3.97 (m, 2H), 3.70 (m,4H), 3.05 (m, 1H), 2.68 (d, J=8 Hz, 2H), 2.45 (m, 4H). To a solution ofthis amine (406 mg, 1.15 mmol) in DME (7 mL)/Na₂CO₃ (2M, 1.7 mL) wasadded 3-formyl-phenylboronic acid (259 mg, 1.9 mmol) and Pd(P(Ph)₃)₄ (60mg). The flask was then fitted with a reflux condenser, purged withargon and heated to 85° C. O/N. The reaction was worked up by pouringinto 1 M NaOH (150 mL) and vacuum isolating the resultant solids. Thecrude material was purified by plugging through SiO₂ (50% Acetone inEtOAc) to give 380 mg (1 mmol, 85% yield) of aldehyde which was used asis. ¹H NMR (500 MHz, CDCl₃) δ=10.1 (s, 1H), 8.13 (s, 1H), 7.93 (d, J=8Hz, 1H), 7.89 (d, J=8 Hz, 1H), 7.66 (t, J=8 Hz, 1H), 7.18 (s, 1H), 6.05(s, 1H), 4.46 (t, J=8 Hz, 2H), 4.04 (m, 2H), 3.72 (t, J=4 Hz, 4H), 3.10(m, 1H), 2.72 (d, J=7 Hz, 2H), 2.47 (m, 4H). To a stirring solution ofthis aldehyde (380 mg, 1.0 mmol) and Rupert's reagent (220 μL, 1.5 mmol)in THF (3 mL) at 0° C. was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After30 min at low temperature the cold bath was removed and the reaction wasallowed to come to RT. After 3 hours the reaction was concentrated invacuo and the flask was charged with THF (20 mL). To this an excess ofTBAF was added and the reaction was left to stir. Once the deprotectionwas complete EtOAc (100 mL) was added and the reaction was washed with,brine, dried with MgSO₄ and concentrated in vacuo. The crude materialwas purified by flash column chromatography (80% EtOAc, 2% TEA, balanceHex) to give 100 mg (22% yield). ¹H NMR (500 MHz, CDCl₃) δ=7.72 (s, 1H),7.65 (dm, J=8 Hz, 1H), 7.52 (m, 2H), 7.15 (s, 1H), 6.03 (s, 1H), 5.13(q, J=5 Hz, 1H), 4.44 (t, J=8 Hz, 2H), 4.01 (m, 2H), 3.72 (t, J=6 Hz,4H), 3.09 (m, 1H), 2.92 (s, br, 1H), 2.71 (d, j=8 Hz, 2H), 2.47 (m, 4H).

To a stirring solution of1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (280 mg, 1.04mmol) dissolved in DCM (10 mL) was added Dess-Martin reagent (Oakwood)(571 mg, 1.3 mmol) dissolved in DCM (4 mL). After 1 hour the reactionhad become turbid and a precipitate had formed. The material was pouredin to 1 M NaOH and extracted with TBME to give the corresponding ketone.¹H NMR (500 MHz, CDCl₃) δ=7.40 (s, 1H), 6.13 (s, 1H), 5.10 (s, 4H). To astirring solution of the ketone (226 mg, 0.8 mmol) in DCM (4 mL) wasadded pyrrolidine (75 μL, 0.9 mmol), glacial acetic acid (45 μL, 0.9mmol) and sodium triacetoxyborohydride (250 mg, 1.26 mmol). When thereaction was deemed complete (TLC) it was diluted with EtOAc (100 mL)and washed with sodium hydroxide (1M aq). The organic phase was thenwashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudeamine was purified by flash chromatography (EtOAc) to give 216 mg (0.7mmol, 79% yield) of material. ¹H NMR (500 MHz, CDCl₃) δ=7.18 (s, 1H),5.89 (s, 1H), 4.28 (m, 2H), 4.21 (m, 2H), 3.53 (m, 1H), 2.57 (m, 4H),1.58 (m, 4H). To a solution of this amine (216 mg, 0.7 mmol) in DME (4mL)/Na₂CO₃ (2M, 1.05 mL) was added 3-formyl-phenylboronic acid (158 mg,1.05 mmol) and Pd(P(Ph)₃)₄ (60 mg). The flask was then fitted with areflux condenser, purged with argon and heated to 85° C. O/N. Thereaction was worked up by pouring into 1 M NaOH (150 mL) and vacuumisolating the resultant solids. The crude material was purified byplugging through SiO₂ (EtOAc 1% MeOH) to give 212 mg of aldehyde whichwas used as is. ¹H NMR (500 MHz, CDCl₃) δ=10.1 (s, 1H), 8.11 (s, 1H),7.93 (d, J=8 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.63 (m 1H), 7.17 (s, 1H),6.05 (s, 1H), 4.43 (m, 2H), 4.24 (m, 2H), 3.53 (m, 1H), 2.58 (m, 4H),1.85 (m, 4H). To a stirring solution of this aldehyde (212 mg, 0.6 mmol)and Rupert's reagent (266 μL, 1.8 mmol) in THF (3 mL) at 0° C. was addedTBAF (0.2 mL, 1 M THF, 0.2 mmol).

After 30 min at low temperature the cold bath was removed and thereaction was allowed to come to RT. After 3 hours the reaction wasconcentrated in vacuo and the flask was charged with THF (20 mL). Tothis an excess of TBAF was added and the reaction was left to stir. Oncethe deprotection was complete EtOAc (100 mL) was added and the reactionwas washed with saturated NH₄Cl, brine, and then dried with MgSO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (2% MeOH in DCM) to give 16 mg (6.2% yield). ¹H NMR (500MHz, DMSO) δ=7.89 (s, 1H), 7.81 (dm, J=8 Hz, 1H), 7.56 (m, 2H), 7.31 (s,1H), 6.96 (d, J=6 Hz, 1H), 6.25 (s, 1H), 5.28 (m 1H), 4.38 (m, 2H), 4.16(m, 2H), 3.52 (m, 1H), 2.51 (m, 4H), 1.73 (m, 4H).

To a stirring solution of(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)methanol (500 mg,1.76 mmol) in DCM (20 mL) was added Dess-Martin periodane (1.1 g, 2.64mmol) and the solution was left to stir for 1 hour. At this time thereaction was diluted with EtOAc (100 mL) and washed with sodiumcarbonate (sat.). The organic layer was dried with MgSO₄, andconcentrated in vacuo. The crude material was purified by pluggingthrough SiO₂ (DCM) to give 420 mg (1.49 mmol, 84% yield) of aldehyde. ¹HNMR (500 MHz, CDCl₃) δ=9.96 (d, J=2 Hz, 1H), 7.26 (s, 1H), 5.96 (s, 1H),4.47 (m, 4H), 3.7 (m, 1H). To a stirring solution of this aldehyde (316mg, 1.1 mmol) in DCM (5 mL) was added pyrrolidine (118 μL, 1.45 mmol)followed by sodium triacetoxyborohydride (385 mg, 1.82 mmol). When thereaction was deemed complete (monitored by TLC), it was diluted with DCM(100 mL) and washed with water (50 mL), sodium hydroxide (1M, 50 mL),then dried with MgSO₄ and concentrated in vacuo to give 425 mg. Thematerial was used without further purification. ¹H NMR (500 MHz, CDCl₃)δ=7.14 (s, 1H), 5.83 (s, 1H), 4.40 (m, 2H), 3.98 (m, 2H), 3.04 (m, 1H),2.76 (d, J=8 Hz, 2H), 2.51 (m, 4H), 1.79 (m, 4H). To a solution of amine(425 mg, 1.26 mmol) in DME (8 mL)/Na₂CO₃ (2M, 1.9 mL) was added3-formyl-phenylboronic acid (283 mg, 1.9 mmol) and Pd(P(Ph)₃)₄ (66 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 85° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by plugging through SiO₂ (50% Acetone in EtoAc) togive 274 mg (0.75 mmol, 75% yield) of aldehyde which was used as is. ¹HNMR (500 MHz, CDCl₃) δ=10.10 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=8 Hz,1H), 7.89 (d, J=8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 717 (s, 1H), 6.03 (s,1H), 4.48 (t, J=8 Hz, 2H), 4.05 (m, 2H), 3.10 (m, 1H), 2.81 (d, J=8 Hz,2H), 2.54 (m, 4H), 1.80 (m, 4H). To a stirring solution of this aldehyde(274 mg, 0.75 mmol) and Rupert's reagent (166 μL, 1.1 mmol) in THF (3mL) at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30 min atlow temperature the cold bath was removed and the reaction was allowedto come to RT. After 3 hours the reaction was concentrated in vacuo andthe flask was charged with THF (20 mL). To this an excess of TBAF wasadded and the reaction was left to stir. Once the deprotection wascomplete EtOAc (100 mL) was added and the reaction was washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(50% EtOAc, 49% Hex, 1% TEA) to give 70 mg (22% yield). ¹H NMR (500 MHz,DMSO-D₆) δ=7.88 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.59 (dm, J=7 Hz, 1H),7.54 (t, J=8 Hz, 1H), 7.30 (s, 1H), 6.96 (d, J=5 Hz, 1H), 6.24 (s, 1H),5.28 (m, 1H), 4.38 (m, 2H), 3.97 (m, 2H), 3.00 (m, 1H), 2.74 (d, J=7 Hz,2H), 2.45 (m, 4H), 1.68 (m, 4H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (2.013 g, 7.24 mmol) and (S)-ethylpyrrolidine-2-carboxylate hydrochloride salt (1.43 g, 7.96 mmol) weremassed into a tube. The tube was evacuated and flushed with argon forthree cycles. NMP (10 mL) and DIPEA (3.5 mL, 19.9 mmol) were then addedand the tube was sealed and heated to 50° C. overnight. Upon cooling toroom temperature the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was back-extracted withEtOAc. The combined organic layers were then washed with water (5×),brine, dried (Na₂SO₄), filtered and concentrated to give an oil. Thecrude oil was then purified via flash column chromatography (15%EtOAc/hexane) to afford 0.6105 g (25% yield) of aniline. The aniline(1.696 g, 4.9 mmol) was dissolved in DCM (20 mL) and cooled to −78° C.DIBAL (12.5 mL, 1.0 M solution in hexanes) was added dropwise and thenthe reaction was allowed to warm to room temperature overnight. Thereaction was quenched with MeOH and then Na₂SO₄ was added and themixture was stirred for 30 minutes before filtering through Celite. Theorganic phase was diluted with EtOAc and water. The layers wereseparated and the organic layer was washed with H₂O (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified viachromatography (30% EtOAc/hexane) to give 1.294 g (87% yield) of theprimary alcohol. The primary alcohol (0.9956 g, 3.34 mmol) was dissolvedin DCM (100 mL) and DMP (2.1249 g, 5.0 mmol) was added. The reaction wasstirred for 2 hours and then it was quenched with saturated NaHCO₃ (aq)and excess Na₂SO₄ (8.0 g) was added and the mixture was stirred untilall solids dissolved. This mixture was then extracted with DCM and thecombined organic layer was dried (Na₂SO₄), filtered and concentrated.Purification (20% EtOAc/hexane column) afforded 0.6471 g (65% yield) ofthe aldehyde. This aldehyde (0.206 g, 0.696 mmol) and cyclobutylaminehydrolchloride (0.0794 g, 0.738 mmol) were dissolved in methanol (3 mL)and TEA (0.19 mL, 1.39 mmol) was added. This material was stirred for 24hours and was then cooled to 0° C. To this mixture was then added NaBH₄(0.0685 g, 1.81 mmol) portionwise. The mixture was stirred for 60minutes and then was quenched with 1N NaOH (aq). The mixture wasextracted with EtOAc (3×) and the combined organics were washed with H₂O(3×), brine, dried (Na₂SO₄), filtered and concentrated to give the crudeamine To a solution of this amine in THF (5 mL) at 0° C. was added TEA(0.19 mL, 1.39 mmol), DMAP (a crystal) and then BOC₂O (0.1822 g, 0.835mmol). The reaction was stirred at 0° C. while monitoring by TLC. It wasthen quenched with H₂O and extracted with EtOAc. The combined organicswere washed with H₂O (3×), brine, dried (Na₂SO₄), filtered andconcentrated to give the crude carbamate. This carbamate and3-formylphenylboronic acid (0.1094 g, 0.73 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (1.6 mL)and 2M Na₂CO₃ (1.1 mL, 2.09 mmol) were then added followed by Pd(PPh₃)₄(0.0402 g, 0.0348 mmol). The tube was then sealed and heated to 80° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil was then dissolved in THF (4 mL) and cooledto 0° C. CF₃TMS (0.21 mL, 1.39 mmol) was added followed by TBAF (0.07mL, 1.0 M solution in THF). The reaction was then stirred for 60 minutesbefore re-cooling to 0° C. and 4N HCl (aq) was added and stirred for 60minutes. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was basified. The aqueous layer was thenre-extracted with EtOAc. The combined organic layers were was withwater, brine, dried (Na₂SO₄), filtered and concentrated to give thetrifluorocarbinol, as a mixture of diastereomers. This crude materialwas then dissolved in DCM (15 mL) and cooled to 0° C. TFA (0.53 mL) wasadded and the mixture was stirred for 36 hours before quenching withsaturated NaHCO₃(aq). This mixture was extracted with DCM (5×) and thecombined organics were dried with NA₂SO₄, filtered and thenconcentrated. This crude material was purified via 5% MeOH/DCM column toafford 0.130 g of the free amine. This material was then dissolved inMeOH at 0° C. and treated with a large excess of methanolic HCl. Thereaction mixture was stirred for 30 minutes and then concentrated toproduce 0.081 g (24% yield, 8 steps) of TRV-1458. ¹H NMR (MeOD, 700 MHz)δ=7.83 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.52 (t,J=7.6 Hz, 1H), 7.26 (s, 1H), 6.43 (s, 1H), 5.16 (q, J=7.1 Hz, 1H), 3.87(m, 1H), 3.78-3.77 (m, 1H), 3.52-3.50 (m, 1H), 3.30 (s, 2H), 3.25 (dd,J=12.5, 2.1 Hz, 1H), 3.05 (t, J=11.0 Hz, 1H), 2.36-2.20 (m, 9H),1.99-1.90 (m, 2H).

4,6-dibromobenzo[c][1,2,5]oxadiazole (1.1509 g, 4.14 mmol) andN-methyl-1-(thiazol-2-yl)methanamine (4.97 mmol) were massed into atube. The tube was evacuated and flushed with argon for three cycles.NMP (6 mL) and DIPEA (0.94 mL, 5.38 mmol) were then added and the tubewas sealed and heated to 100° C. overnight. Upon cooling to roomtemperature the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was back-extracted with EtOAc. Thecombined organic layers were then washed with water (5×), brine, dried(Na₂SO₄), filtered and concentrated to give an oil. The crude oil wasthen purified via flash column chromatography (30% EtOAc/hexane) toafford 0.1872 g (14% yield) of aniline. This aniline (0.1872 g, 0.58mmol) and 3-formylphenylboronic acid (0.0899 g, 0.60 mmol) were massedinto a tube. The tube was evacuated and purged with argon (3×). DME (1.5mL) and 2M Na₂CO₃ (0.9 mL, 1.74 mmol) were then added followed byPd(PPh₃)₄ (0.0335 g, 0.029 mmol). The tube was then sealed and heated to85° C. overnight. Upon cooling to room temperature the mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was back-extracted with EtOAc. The combined organic layers werethen washed with water (5×), brine, dried (Na₂SO₄), filtered andconcentrated to give an oil. This crude oil was then dissolved in THF (4mL) and cooled to 0° C. CF₃TMS (0.17 mL, 1.16 mmol) was added followedby TBAF (0.06 mL, 1.0 M solution in THF). The reaction was then stirredfor 60 minutes before re-cooling to 0° C. and 4N HCl (aq) was added andstirred for 60 minutes. The mixture was diluted with water and EtOAc.The layers were separated and the aqueous layer was basified. Theaqueous layer was then re-extracted with EtOAc. The combined organiclayers were was with water, brine, dried (Na₂SO₄), filtered andconcentrated to give a crude oil. This material was purified via flashcolumn chromatography with step-gradient (100% DCM to 0.5% MeOH/DCM) toafford 0.0339 g (14% yield, 3 steps) of TRV-1459. ¹H NMR (CDCl3, 700MHz) δ=7.77 (d, J=3.2 Hz, 1H), 7.73 (s, 1H), 7.66 (dt, J=7.2, 1.6 Hz,1H), 7.55-7.51 (m, 2H), 7.31 (s, 1H), 7.30 (d, J=3.2 Hz, 1H), 6.46 (s,1H), 5.46 (s, 2H), 5.13 (q, J=6.6 Hz, 1H), 3.32 (s, 3H).

6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine(1.00 g, 2.97 mmol) and 3-carboxyphenylboronic acid (0.5176 g, 3.12mmol) were massed into a tube. The tube was evacuated and purged withargon (3×). DME (8.9 mL) and 2M Na₂CO₃ (6.0 mL, 11.9 mmol) were thenadded followed by Pd(PPh₃)₄ (0.1733 g, 0.15 mmol). The tube was thensealed and heated to 100° C. overnight. Upon cooling to room temperaturethe mixture was diluted with water and EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc. The combinedorganic layers were then washed with water (5×), brine, dried (Na₂SO₄),filtered and concentrated to give the crude material. This was purifiedvia 5% MeOH/DCM column to afford 1.0873 g (97% yield, 90% chemicalpurity) of the acid. A mixture of the acid (0.3774 g, 1.0 mmol),pyrrolidine (0.083 mL, 1.0 mmol) and TEA (0.35 mL, 2.5 mmol) werestirred in EtOAc (10 mL) and cooled in an ice bath. The T3P solution(0.7636 g, w/w in EtOAc) was added dropwise. Once the addition wascomplete the reaction was allowed to warm to room temperature. Thereaction was then quenched with water and extracted with EtOAc. Thecombined organic layers were washed with water (3×), brine, dried(Na₂SO₄), filtered and concentrated. The crude material was thenpurified by two successive columns (75% EtOAc/hexane and then 70%EtOAc/hexane) to give 0.1436 g (33% yield, 96% c.p.) of TRV-1460. ¹H NMR(CDCl3, 500 MHz) δ=7.75 (s, 1H), 7.65 (d, J=10 Hz, 1H), 7.55 (d, J=10Hz, 1H), 7.52-7.48 (m, 1H), 7.26-7.23 (m, 3H), 7.01 (t, J=10 Hz, 2H),6.35 (s, 1H), 5.12 (s, 2H), 3.68 (t, J=5 Hz, 2H), 3.45 (t, J=5 Hz, 2H),2.02-1.95 (m, 2H), 1.92-1.86 (m, 2H).

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidine-3-carboxylic acid (1.5g, 5 mmol) was dissolved in THF (50 mL) and cooled to 0° C. To this wasadded BH₃-THF (10 mL, 10 mmol). The reaction was allowed to come to roomtemperature overnight. The next day the reaction was quenched with AcOHand extracted into EtOAc. The organic layer was washed with 1 M NaOHuntil the washings remained litmus blue and then concentrated in vacuo.The crude material was fused to SiO₂ and purified by flash columnchromatography (3:2 Hex:EtOAc) to give 800 mg of primary alcohol (56%yield). ¹H NMR (500 MHz, CDCl₃) δ=7.05 (s, 1H), 6.11 (s, 1H), 5.30 (s,1H), 4.11 (t, J=8 Hz, 2H), 3.85 (m, 4H), 3.00 (m, 1H). To a stirringsolution of the alcohol (500 mg, 1.76 mmol) in DCM (20 mL) was addedDess-Martin periodane (1.1 g, 2.64 mmol) and the solution was left tostir for 1 hour. At this time the reaction was diluted with EtOAc (100mL) and washed with sodium carbonate (sat.). The organic layer was driedwith MgSO₄, and concentrated in vacuo. The crude material was purifiedby plugging through SiO₂ (DCM) to give 420 mg (1.49 mmol, 84% yield) ofaldehyde. ¹H NMR (500 MHz, CDCl₃) δ=9.96 (d, J=2 Hz, 1H), 7.26 (s, 1H),5.96 (s, 1H), 4.47 (m, 4H), 3.7 (m, 1H). To a 0° C. stirring solution ofthis aldehyde (420 mg, 1.5 mmol) in THF (10 mL) was addedmethylmagnesium bromide (1M, 1.8 mL). After 10 min at reducedtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 1 hour the reaction was cooled back to 0° C. andsaturated NH₄Cl was cautiously added. The reaction mixture was thendiluted with EtOAc (100 mL) and the phases were separated. The organicphase was washed with brine, dried with MgSO₄ and concentrated in vacuo.The crude material was fused to SiO₂ (4 g) and gradient flashed (0-2%MeOH in DCM) to give 380 mg (1.27 mmol, 85% yield) of secondary alcohol.To a solution of the secondary alcohol (approx. 190 mg, 0.65 mmol)dissolved in THF (5 mL) and cooled to 0° C. was added NaH 60% in oil(100 mg, 3 mmol). Once the initial bubbling had subsided MeI (200 μL, 3mmol) was added dropwise the reaction mixture was left to come to RT.After 18 h the reaction was cooled back to 0° C. and NH₄Cl wascautiously added. The reaction mixture was extracted with EtOAc (3×50mL), washed with brine (150 mL) and concentrated in vacuo. The crudematerial was purified by plugging through SiO₂ (80% DCM in Hex) to give160 mg (78% yield) of methyl ether. To a solution of the methyl ether(160 mg, 0.5 mmol) in DME (4 mL)/Na₂CO₃ (2 M, 0.75 mL) was added3-formyl-phenylboronic acid (113 mg, 1.5 mmol) and Pd(P(Ph)₃)₄ (40 mg).The flask was then fitted with a reflux condenser, purged with argon andheated to 85° C. O/N. The reaction was worked up by pouring into 1 MNaOH (150 mL) and vacuum isolating the resultant solids. The crudematerial was purified by plugging through SiO₂ (DCM/5% EtOAc) to give150 mg of aldehyde which was used as is. To a stirring solution of thealdehyde (150 mg, 0.4 mmol) and Rupert's reagent (98 μL, 0.7 mmol) inTHF (2 mL) at 0° C. was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After 30min at low temperature the cold bath was removed and the reaction wasallowed to come to RT. After 3 hours the reaction was concentrated invacuo and the flask was charged with THF (20 mL). To this an excess ofTBAF was added and the reaction was left to stir. Once the deprotectionwas complete EtOAc (100 mL) was added and the reaction was washed withsaturated NH₄Cl, brine, and then dried with MgSO₄ and concentrated invacuo. The crude material was purified by flash column chromatography(30% EtOAc in Hexane) to give 37 mg (23% yield) of TRV-1461, a 1:1:1:1mixture of diastereomers due to the two chiral centers. ¹H NMR (500 MHz,DMSO) δ=7.72 (s, 1H), 7.65 (d, J=7 Hz, 1H), 7.52 (m, 2H), 7.13 (s, 1H),6.02 (s, 1H), 5.13 (m, 1H), 4.38 (m, 2H), 4.19 (m, 1H), 4.09 (m, 1H),3.55 (p, J=6 Hz, 1H), 3.39 (s, 3H), 2.88 (m, 1H), 2.71 (s, br, 1H), 1.78(d, J=6 Hz, 3H).

To a stirring solution of1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-ol (730 mg, 2.7 mmol)dissolved in DCM (10 mL) was added Dess-Martin reagent (Oakwood) (1.26g, 2.97 mmol) dissolved in DCM (10 mL). After 1 hour the reaction hadbecome turbid and a precipitate had formed. The material was poured into 1 M NaOH and extracted with TBME to give the corresponding ketone. ¹HNMR (500 MHz, CDCl₃) δ=7.40 (s, 1H), 6.13 (s, 1H), 5.10 (s, 4H). To astirring solution of the ketone (300 mg, 1.1 mmol) in DCM (4 mL) wasadded morpholine (160 μL, 1.23 mmol), glacial acetic acid (65 μL, 1.1mmol) and sodium triacetoxyborohydride (360 mg, 1.68 mmol). When thereaction was deemed complete (TLC) it was diluted with EtOAc (100 mL)and washed with sodium hydroxide (1M aq). The organic phase was thenwashed with brine, dried with MgSO₄ and concentrated in vacuo. The crudeamine was purified by flash chromatography (EtOAc) to give 470 mg (1.4mmol, 52% yield) of material. To a solution of this amine (470 mg, 1.4mmol) in DME (5 mL)/Na₂CO₃ (2M, 2 mL) was added 3-formyl-phenylboronicacid (180 mg, 1.05 mmol) and Pd(P(Ph)₃)₄ (80 mg). The flask was thenfitted with a reflux condenser, purged with argon and heated to 85° C.O/N. The reaction was worked up by pouring into 1 M NaOH (150 mL) andvacuum isolating the resultant solids. The crude material was purifiedby plugging through SiO₂ (EtOAc 1% MeOH) to give 300 mg of aldehydewhich was used as is. To a stirring solution of this aldehyde (300 mg,0.8 mmol) and Rupert's reagent (240 μL, 1.6 mmol) in THF (3 mL) at 0° C.was added TBAF (0.2 mL, 1 M THF, 0.2 mmol). After 30 min at lowtemperature the cold bath was removed and the reaction was allowed tocome to RT. After 3 hours the reaction was concentrated in vacuo and theflask was charged with THF (20 mL). To this an excess of TBAF was addedand the reaction was left to stir. Once the deprotection was completeEtOAc (100 mL) was added and the reaction was washed with saturatedNH₄Cl, brine, and then dried with MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash column chromatography (2% MeOH inDCM) to give 40 mg (9% yield). ¹H NMR (500 MHz, DMSO) δ=7.71 (s, 1H),7.63 (d, J=7 Hz, 1H), 7.51 (m, 2H), 7.16 (s, 1H), 6.06 (s, 1H), 5.13 (m,1H), 4.41 (t, J=8 Hz, 2H), 4.18 (m, 2H), 3.77 (m, 4H), 3.42 (p, J=6 Hz,1H), 2.87 (s, broad, 1H), 2.48 (m, 4H).

6-bromo-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[c][1,2,5]oxadiazole(0.3366 g, 0.958 mmol) and 2-formylthiophene-4-boronic acid (0.1794 g,1.15 mmol) were massed into a tube. The tube was evacuated and purgedwith argon (3×). DME (2.1 mL) and 2M Na₂CO₃ (1.4 mL, 2.87 mmol) werethen added followed by Pd(PPh₃)₄ (0.0554 g, 0.048 mmol). The tube wasthen sealed and heated to 100° C. overnight. Upon cooling to roomtemperature the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was back-extracted with EtOAc. Thecombined organic layers were then washed with water (5×), brine, dried(Na₂SO₄), filtered and concentrated to give an oil. This crude oil wasthen dissolved in THF (5 mL) and cooled to 0° C. CF₃TMS (0.21 mL, 1.44mmol) was added followed by TBAF (0.1 mL, 1.0 M solution in THF). Thereaction was then stirred for 60 minutes before re-cooling to 0° C. and4N HCl (aq) was added and stirred for 60 minutes. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was basified. The aqueous layer was then re-extracted with EtOAc.The combined organic layers were washed with water, brine, dried(Na₂SO₄), filtered and concentrated to give a crude oil. This materialwas purified via flash column chromatography (5% MeOH/DCM) to afford0.067 g (15% yield, 3 steps) of TRV-1463 as a yellow solid. ¹H NMR(DMSO, 700 MHz) δ=8.29 (d, J=1.0 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 1H),7.37 (d, J=6.0 Hz, 1H), 6.83 (s, 1H), 5.52-5.48 (m, 1H), 4.22 (br s,2H), 3.13 (t, J=12 Hz, 2H), 2.59 (br s, 4H), 2.32-2.30 (m, 1H),2.02-2.01 (m, 2H), 1.71 (s, 4H), 1.62-1.61 (m, 2H).

6-bromo-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[c][1,2,5]oxadiazole(0.3368 g, 0.958 mmol) and 5-formyl-2-thienyl-boronic acid (0.1793 g,1.15 mmol) were massed into a tube. The tube was evacuated and purgedwith argon (3×). DME (2.1 mL) and 2M Na₂CO₃ (1.4 mL, 2.87 mmol) werethen added followed by Pd(PPh₃)₄ (0.0554 g, 0.048 mmol). The tube wasthen sealed and heated to 100° C. overnight. Upon cooling to roomtemperature the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was back-extracted with EtOAc. Thecombined organic layers were then washed with water (5×), brine, dried(Na₂SO₄), filtered and concentrated to give an oil. This crude oil wasthen dissolved in THF (5 mL) and cooled to 0° C. CF₃TMS (0.28 mL, 1.92mmol) was added followed by TBAF (0.1 mL, 1.0 M solution in THF). Thereaction was then stirred for 60 minutes before re-cooling to 0° C. and4N HCl (aq) was added and stirred for 60 minutes. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was basified. The aqueous layer was then re-extracted with EtOAc.The combined organic layers were washed with water, brine, dried(Na₂SO₄), filtered and concentrated to give a crude oil. This materialwas purified via flash column chromatography (10% MeOH/DCM). The purityafter the first column was inadequate so the separation was repeatedwith a 5% MeOH/DCM column to afford 0.060 g (14% yield, 3 steps) ofTRV-1464. ¹H NMR (DMSO, 700 MHz) δ=7.77 (d, J=5 Hz, 1H), 7.56 (s, 1H),7.42 (d, J=5 Hz, 1H), 7.28 (d, J=5 Hz, 1H), 6.76 (s, 1H), 5.59-5.55 (m,1H), 4.24 (d, J=10 Hz, 2H), 3.17 (d, J=10 Hz, 2H), 2.60 (br s, 4H), 2.37(br s, 1H), 2.05-2.02 (m, 2H), 1.72 (br s, 4H), 1.64-1.62 (m, 2H).

A mixture of dibromobenzofurazan (0.500 g, 1.8 mmol),N1,N1,N3-trimethylpropane-1,3-diamine (0.28 mL, 1.9 mmol) and DIPEA(0.31 mL, 1.8 mmol) in NMP (2 mL) was heated to 100° C. overnight. Aftercooling to room temperature, the mixture was diluted with EtOAc andwater. After the layers were separated, the aqueous layer was basifiedand extracted with EtOAc (3×). The combine organic layers were washedwith water, brine, dried (MgSO₄), filtered and concentrated to give thecrude aniline. This material was purified via 10% MeOH/DCM column toafford 0.3988 g of aniline. This aniline (0.3988 g, 1.27 mmol) and3-formylphenylboronic acid (0.2488 g, 1.66 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (2.8 mL)and 2M Na₂CO₃ (1.9 mL, 3.8 mmol) were then added followed by Pd(PPh₃)₄(0.074 g, 0.064 mmol). The tube was then sealed and heated to 100° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil was then dissolved in THF (5 mL) and cooledto 0° C. CF₃TMS (0.38 mL, 2.54 mmol) was added followed by TBAF (0.13mL, 1.0 M solution in THF). The reaction was then stirred for 60 minutesbefore re-cooling to 0° C. and 4N HCl (aq) was added and stirred for 60minutes. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was basified. The aqueous layer was thenre-extracted with EtOAc. The combined organic layers were washed withwater, brine, dried (Na₂SO₄), filtered and concentrated to give a crudeoil. This material was purified via flash column chromatography (10%MeOH/DCM) to afford 0.061 g (12% yield, 2 steps) of TRV-1465. ¹H NMR(DMSO, 500 MHz) δ=7.89 (s, 1H), 7.81 (d, J=10 Hz, 1H), 7.59-7.53 (m,2H), 7.29 (s, 1H), 6.95 (d, J=5 Hz, 1H), 6.40 (s, 1H), 5.31-5.25 (m,1H), 3.92 (t, J=10 Hz, 2H), 3.24 (s, 3H), 2.24 (t, J=10 Hz, 2H), 2.08(s, 6H), 1.77-1.71 (m, 2H).

A mixture of dibromobenzofurazan (0.4669 g, 1.68 mmol),N,N-dimethylpiperidin-4-amine (0.2263 g, 1.76 mmol) and DIPEA (0.29 mL,1.68 mmol) in NMP (3 mL) was heated to 95° C. overnight. After coolingto room temperature, the mixture was diluted with EtOAc and water. Afterthe layers were separated, the aqueous layer was basified and extractedwith EtOAc (3×). The combine organic layers were washed with water,brine, dried (MgSO₄), filtered and concentrated to give the crudeaniline. This material was purified via 5% MeOH/DCM column to afford0.2221 g of aniline. This aniline (0.2221 g, 0.68 mmol) and3-formylphenylboronic acid (0.1334 g, 0.89 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (3.0 mL)and 2M Na₂CO₃ (2.0 mL, 4 mmol) were then added followed by Pd(PPh₃)₄(0.039 g, 0.034 mmol). The tube was then sealed and heated to 100° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil was then dissolved in THF (5 mL) and cooledto 0° C. CF₃TMS (0.20 mL, 1.36 mmol) was added followed by TBAF (0.07mL, 1.0 M solution in THF). The reaction was then stirred for 60 minutesbefore re-cooling to 0° C. and 4N HCl (aq) was added and stirred for 60minutes. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was basified. The aqueous layer was thenre-extracted with EtOAc. The combined organic layers were washed withwater, brine, dried (Na₂SO₄), filtered and concentrated to give a crudeoil. This material was purified via flash column chromatography (10%MeOH/DCM) to afford 0.061 g (24% yield, 2 steps) of TRV-1466. ¹H NMR(DMSO, 700 MHz) δ=7.90 (s, 1H), 7.83 (d, J=7 Hz, 1H), 7.59 (d, J=7 Hz,1H), 7.55 (t, J=7 Hz, 1H), 7.51 (d, J=3 Hz, 1H), 6.96 (d, J=3 Hz, 1H),6.73 (s, 1H), 5.30-5.27 (m, 1H), 4.33 (d, J=7 Hz, 2H), 3.05 (t, J=14 Hz,2H), 2.41-2.39 (m, 1H), 2.23 (s, 6H), 1.93 (d, J=14 Hz, 2H), 1.61-1.54(m, 2H).

6-bromo-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[c][1,2,5]oxadiazole(1 g, 2.8 mmol) and (2-formylphenyl)boronic acid (0.554 g, 3.6 mmol)were massed into a tube. The tube was evacuated and purged with argon(3×). DME (6 mL) and 2M Na₂CO₃ (4.2 mL, 8.4 mmol) were then addedfollowed by Pd(PPh₃)₄ (0.160 g, 0.14 mmol). The tube was then sealed andheated to 100° C. overnight. Upon cooling to room temperature themixture was diluted with water and EtOAc. The layers were separated andthe aqueous layer was back-extracted with EtOAc. The combined organiclayers were then washed with water (5×), brine, dried (Na₂SO₄),filtered, concentrated and subjected to flash column chromatography (5%MeOH/DCM) to afford 0.95 g of2-(7-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzaldehyde.This aldehyde was then dissolved in THF (15 mL) and cooled to 0° C.CF₃TMS (0.738 mL, 5.06 mmol) was added followed by TBAF (0.25 mL, 1.0 Msolution in THF). The cooling batch was removed and the reaction wasstirred for 30 min. The reaction was then recooled and TBAF (0.30 mL,1.0 M solution in THF) was added and the cooling bath removed. Thereaction was then stirred for 60 minutes before re-cooling to 0° C. and4N HCl (aq) was added and stirred for 60 minutes. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was basified. The aqueous layer was then re-extracted with EtOAc.The combined organic layers were washed with water, brine, dried(Na₂SO₄), filtered and concentrated to give a crude oil. This materialwas purified via flash column chromatography (5% MeOH/DCM) to afford0.550 g (44% yield, 2 steps) of TRV-1467 as a yellow solid. ¹H NMR(DMSO, 500 MHz) δ=7.72 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.36 (d,J=7.5 Hz, 1H), 7.15 (s, 1H) 6.91 (d, J=5 Hz, 1H), 6.33 (s, 1H),5.13-5.11 (m, 1H), 4.16 (br s, 2H), 3.15-3.09 (m, 2H), 2.53-2.49 (m,4H), 2.26 (br s, 1H), 1.99-1.97 (m, 2H), 1.68 (s, 4H), 1.59-1.57 (m,2H).

6-bromo-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[c][1,2,5]oxadiazole(0.5 g, 1.4 mmol) and (2-formylphenyl)boronic acid (0.277 g, 1.8 mmol)were massed into a tube. The tube was evacuated and purged with argon(3×). DME (6 mL) and 2M Na₂CO₃ (4.2 mL, 8.4 mmol) were then addedfollowed by Pd(PPh₃)₄ (0.080 g, 0.07 mmol). The tube was then sealed andheated to 100° C. overnight. Upon cooling to room temperature themixture was diluted with water and EtOAc. The layers were separated andthe aqueous layer was back-extracted with EtOAc. The combined organiclayers were then washed with water (5×), brine, dried (Na₂SO₄),filtered, concentrated and subjected to flash column chromatography (5%MeOH/DCM) to afford 0.53 g of4-(7-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzaldehyde.This aldehyde was then dissolved in THF (5 mL) and cooled to 0° C.CF₃TMS (0.392 mL, 2.8 mmol) was added followed by TBAF (0.140 mL, 1.0 Msolution in THF). The cooling batch was removed and the reaction wasstirred for 30 min. The reaction was then stirred for 60 minutes beforere-cooling to 0° C. and 4N HCl (aq) was added and stirred for 60minutes. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was basified. The aqueous layer was thenre-extracted with EtOAc. The combined organic layers were washed withwater, brine, dried (Na₂SO₄), filtered and concentrated to give a crudeoil. This material was purified via flash column chromatography (5%MeOH/DCM) to afford 0.270 g (43% yield, 2 steps) of TRV-1468 as a yellowsolid. ¹H NMR (DMSO, 500 MHz) δ=7.84 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0Hz, 2H), 7.56 (s, 1H), 6.94 (d, J=5.5 Hz, 1H), 6.77 (s, 1H), 5.29-5.23(m, 1H), 4.23 (br s, 2H), 2.49 (brs, 3H), 2.25 (br s, 1H), 2.01-1.99 (m,2H) 1.69 (br s, 4H), 1.61-1.59 (m, 2H).

A mixture of 4,6-dibromobenzo[c][1,2,5]oxadiazole (1.6246 g, 5.8 mmol),N-methyl-3-(pyrrolidin-1-yl)propan-1-amine (approximately 7.6 mmol) andDIPEA (1.1 mL, 5.8 mmol) in NMP (6 mL) was heated to 90° C. overnight.After cooling to room temperature, the mixture was diluted with EtOAcand water. After the layers were separated, the aqueous layer wasbasified and extracted with EtOAc (3×). The combine organic layers werewashed with water, brine, dried (MgSO₄), filtered and concentrated togive the crude aniline. This material was purified via 10% MeOH/DCMcolumn to afford 0.5651 g of aniline. This aniline (0.5651 g, 1.67 mmol)and 3-formylphenylboronic acid (0.3253 g, 2.17 mmol) were massed into atube. The tube was evacuated and purged with argon (3×). DME (3.7 mL)and 2M Na₂CO₃ (2.5 mL, 5 mmol) were then added followed by Pd(PPh₃)₄(0.0965 g, 0.084 mmol). The tube was then sealed and heated to 100° C.overnight. Upon cooling to room temperature the mixture was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc. The combined organic layers were then washedwith water (5×), brine, dried (Na₂SO₄), filtered and concentrated togive an oil. This crude oil was then dissolved in THF (5 mL) and cooledto 0° C. CF₃TMS (0.49 mL, 3.34 mmol) was added followed by TBAF (0.17mL, 1.0 M solution in THF). The reaction was then stirred for 60 minutesbefore re-cooling to 0° C. and 4N HCl (aq) was added and stirred for 60minutes. The mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was basified. The aqueous layer was thenre-extracted with EtOAc. The combined organic layers were washed withwater, brine, dried (Na₂SO₄), filtered and concentrated to give a crudeoil. This material was purified via flash column chromatography (5%MeOH/DCM with 6 mL NH₄OH) to afford 0.465 g (64% yield, 2 steps) ofTRV-1469 as orange solid. ¹H NMR (DMSO, 700 MHz) δ=7.72 (s, 1H), 7.60(d, J=7 Hz, 1H), 7.50 (d, J=7 Hz, 1H), 7.47 (t, J=7 Hz, 1H), 7.13 (d,J=3 Hz, 1H), 6.21 (s, 1H), 5.05 (q, J=7 Hz, 1H), 3.94 (t, J=7 Hz, 2H),3.16 (s, 3H), 2.59 (br s, 6H), 1.95-1.91 (m, 2H), 1.81 (br s, 4H).

A mixture of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (3.1436 g, 13.4mmol), 3-azetidinecarboxylic acid (1.76 g, 17.4 mmol) and DIPEA (7.0 mL,40.2 mmol) in NMP (15 mL) was heated to 90° C. overnight. After coolingto room temperature, the mixture was diluted with EtOAc and 2N HCl. Thelayers were separated and the aqueous layer was back-extracted withEtOAc (3×). The combined organic layers were washed with water (3×),brine, dried (MgSO₄), filtered and concentrated to give the crudematerial. This material was then dissolved in EtOAc and extracted with 2N NaOH (3×). The combined aqueous extracts were acidified to pH 1-2 withconcentrated HCl. This suspension was then extracted with EtOAc (3×).The combined organic layers were then washed with water (3×), brine,dried (MgSO₄) filtered and concentrated to afford 3.0657 g of orangesolid. This crude mixture (3.066 g, 10.3 mmol) was dissolved in THF andcooled to −10° C. with a MeOH/ice bath. A 1M solution of BH₃-THF in THF(21 mL, 21 mmol) was added dropwise, producing a bright red solution.The solution was stirred vigorously for 10 minutes and then allowed towarm to room temperature overnight. The reaction was quenched with thedropwise addition of 10 mL of AcOH/H₂O (1:1 v/v). After effervescencesubsided, the mixture was concentrated to remove THF. The aqueousmixture was then basified with 2N NaOH and extracted with EtOAc (2×).The combined organic layers were washed with water, brine, dried(MgSO₄), filtered and concentrated. The material was purified viachromatography (40-50% EtOAc/hexane) to afford 1.942 g of the primaryalcohol. This alcohol (0.9217 g, 3.2 mmol) was suspended in DCM (40 mL)and then Dess-Martin reagent (1.789 g, 4.2 mmol) was added portion wiseand the mixture was stirred for 2.5 hours. The reaction was thenquenched with saturated NaHCO₃ (aq) and excess Na₂S₂O₃, stirring wascontinued until the solids dissolved. This mixture was then extractedwith DCM (3×). The combined organic layers were washed with saturatedNaHCO₃ (aq) and then dried with MgSO₄, before filtering andconcentrating the solution. The crude aldehyde was then purified viachromatography (40% EtOAc/hexane) to provide 0.7704 g of aldehyde. Thealdehyde (0.7411 g, 2.63 mmol) was dissolved in DCE (10 mL) and cooledin an ice bath. Morpholine (0.30 mL, 3.42 mmol) was added dropwise andthe reaction was stirred for 5 minutes before NaBH(OAc)₃ was addedportion wise, and the reaction was allowed to stir overnight. Thereaction was quenched with saturated NaHCO₃ and then extracted with DCM.The combined organics were dried (MgSO₄), filtered and concentrated. Thecrude material was then purified via chromatography (80% EtOAc/hexane)to afford 0.7662 g TRV-1470. ¹H NMR (CDCl₃, 700 MHz) δ=7.19 (s, 1H),5.88 (s, 1H), 4.41 (br s, 2H), 4.00 (br s, 2H), 3.73 (br s, 4H), 3.09(s, 1H), 2.71 (s, 2H), 2.48 (br s, 4H).

TRV-1470 (0.4092 g, 1.16 mmol) and 3-formylphenylboronic acid (0.1829 g,1.22 mmol) were massed into a tube. The tube was evacuated and purgedwith argon (3×). DME (2.6 mL) and 2M Na₂CO₃ (1.8 mL, 3.48 mmol) werethen added followed by Pd(PPh₃)₄ (0.067 g, 0.058 mmol). The tube wasthen sealed and heated to 80° C. overnight. Upon cooling to roomtemperature the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was back-extracted with EtOAc. Thecombined organic layers were then washed with water (5×), brine, dried(Na₂SO₄), filtered and concentrated to give an oil. This crude oil wasthen dissolved in THF (10 mL) and cooled to 0° C. CF₃TMS (0.34 mL, 2.32mmol) was added followed by TBAF (0.12 mL, 1.0 M solution in THF). Thereaction was then stirred for 60 minutes before re-cooling to 0° C. and4N HCl (aq) was added and stirred for 60 minutes. The mixture wasdiluted with water and EtOAc. The layers were separated and the aqueouslayer was basified. The aqueous layer was then re-extracted with EtOAc.The combined organic layers were washed with water, brine, dried(Na₂SO₄), filtered and concentrated to give a crude oil. This materialwas purified via flash column chromatography (3% of a 7 N NH₃ solutionin MeOH/DCM) to afford 0.125 g of TRV 1471 (24% yield, 2 steps). ¹H NMR(CDCl3, 700 MHz) δ=7.78 (d, J=7 Hz, 1H), 7.47 (t, J=7 Hz, 1H), 7.45 (t,J=7 Hz, 1H), 7.30 (d, J=1H), 6.90 (s, 1H), 5.73 (s, 1H), 5.21 (br s,1H), 4.42-4.38 (m, 2H), 3.98 (br s, 2H), 3.71 (br s, 4H), 3.09-3.06 (m,1H), 2.92 (s, 1H), 2.72 (d, J=7 Hz, 2H), 2.48 (br s, 4H).

(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)methanol (1.9573g, 6.89 mmol) was suspended in DCM (85 mL) and Dess-Martin reagent(3.799 g, 8.9 mmol) was added all at once and stirred until completeconsumption of starting material, approximately 90 minutes. The mixturewas then cooled in an ice bath and saturated NaHCO₃ (aq) and Na₂S₂O₃(4.2 g) were added and stirred until all the solids dissolved. Thesolution was then extracted with DCM (3×) and the combined organics werewashed with saturated NaHCO₃ (aq), dried (MgSO₄), filtered andconcentrated. The crude material was purified via column (20-100%EtOAc/hexane gradient) to afford 2.0355 g of aldehyde. The aldehyde wasthen dissolved in DCE (0.28 M solution) and cooled in an ice bath.Pyrrolidine (0.20 mL, 2.4 mmol) was added and stirred for 5 minutes,followed by the addition of NaHB(OAc)₃ (0.7630 g, 3.6 mmol) all at once.The mixture was allowed to warm to room temperature overnight. Aftercooling again in an ice bath, the reaction was quenched with saturatedNaHCO₃ and stirred until effervescence stopped. This mixture was thenextracted with DCM (3×). The combined organic layers were dried (MgSO₄),filtered and concentrated. Ultimately this crude material was purifiedvia chromatography (63-69% MeCN/DCM gradient with 1% TEA additive) toafford TRV-1472. ¹H NMR (CDCl3, 700 MHz) δ=7.18 (s, 1H), 5.88 (s, 1H),4.44 (s, 2H), 4.03 (s, 2H), 3.13 (s, 1H), 2.87 (br s, 2H), 2.61 (br s,4H), 1.86 (s, 4H).

TRV-1472 (0.1350 g, 0.40 mmol) was dissolved in THF (10 mL) under argon,and cooled to −78° C. nBuLi (0.23 mL, 2.0 M solution in cyclohexane) wasadded dropwise and the mixture was stirred for 20 minutes. Methanol(0.16 mL, 4 mmol) was added at −78° C. and the mixture was allowed towarm to 0° C. where it was quenched with saturated NH₄Cl(aq). Thismixture was extracted with EtOAc (3×) and the combined organic layerswere washed with H₂O, brine, dried (MgSO₄), filtered and concentrated.The crude material was purified via chromatography (10-100% EtOAc/Hexanegradient with 5% TEA additive) to afford 0.0585 g (57% yield) ofTRV-1473 as orange oil. ¹H NMR (CDCl3, 700 MHz) δ=7.21 (dd, J=8.4, 7.7Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.84 (d, J=7.7 Hz, 1H), 4.42 (t, J=7.7Hz, 1H), 4.00 (s, 2H), 3.13 (br s, 1H), 2.90 (br s, 2H), 2.62 (br s,4H), 1.88 (s, 4H).

TRV-1472 (0.2281 g, 0.68 mmol) and 2-formylbenzeneboronic acid (0.1070g, 0.71 mmol) were sealed in a tube. The tube was evacuated and purgedwith argon (3 cycles). 2M Na₂CO₃ (1.0 mL, 2.0 M aq solution) was addedalong with DME (1.6 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.0393 g, 0.0034 mmol) was added all at once. The tubewas re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude aldehyde waspurified via chromatography (10-100% EtOAc/hexane gradient, 5% TEAadditive) to afford 0.0753 g of pure material. The aldehyde was thendissolved in THF (5 mL) and cooled in an ice bath. To this solution wasadded CF₃TMS (61 μL, 0.415 mmol) and then TBAF (˜20 μL, 1.0 M solutionin THF). After 5 minutes, the ice bath was removed and the mixture wasstirred until complete conversion of starting material, the mixture wascooled in an ice bath and quenched with 2N HCl(aq). After 30 minutes,the mixture was then made basic with 2N NaOH and extracted with EtOAc(3×). The combined organics were then washed with water, brine, dried(MgSO₄), filtered and concentrated. The crude material was then purifiedvia chromatography (63% EtOAc/hexane with 5% TEA additive) to afford0.0357 g (40% yield) of TRV-1474. ¹H NMR (CDCl3, 700 MHz) δ=7.80 (d,J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.43-7.41 (m, 1H), 7.29-7.27 (m,1H), 6.93 (s, 1H), 5.78 (s, 1H), 5.24 (q, J=7.0 Hz, 1H), 4.47 (br s,1H), 4.38 (s, 1H), 4.13 (br s, 1H), 4.02 (s, 1H), 3.15 (br s, 1H), 2.98(br s, 2H), 2.74 (br s, 4H), 1.91 (br s, 4H).

TRV-1472 (0.2750 g, 0.82 mmol) and (2,4-dichlorophenyl)boronic acid(0.1643 g, 0.86 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) wasadded along with DME (1.8 mL). The solution was degassed for 10 minutesand then Pd(PPh₃)₄ (0.0474 g, 0.041 mmol) was added all at once. Thetube was re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude aldehyde waspurified via chromatography (10-100% EtOAc/hexane gradient, 5% TEAadditive) to afford 0.1821 g (55% yield) of TRV-1475 as orange oil. ¹HNMR (CDCl3, 700 MHz) δ=7.51 (d, J=1.4 Hz, 1H), 7.33 (dd, J=1.4, 8.4 Hz,1H), 7.31 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 5.85 (s, 1H), 4.48 (s, 2H),4.06 (s, 2H), 3.19 (br s, 1H), 2.95 (br s, 2H), 2.64 (br s, 4H), 1.91(br s, 4H).

TRV-1472 (0.2707 g, 0.80 mmol) and pyridin-3-ylboronic acid (0.1033 g,0.84 mmol) were sealed in a tube. The tube was evacuated and purged withargon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) was added alongwith DME (1.8 mL). The solution was degassed for 10 minutes and thenPd(PPh₃)₄ (0.0462 g, 0.04 mmol) was added all at once. The tube wasre-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude aldehyde waspurified via chromatography (1-10% MeOH/DCM gradient, 1% TEA additive)to afford 0.106 g (40% yield) of TRV-1476 as orange oil. ¹H NMR (CDCl3,700 MHz) δ=8.87 (d, J=2.1 Hz, 1H), 8.66 (dd, J=4.9, 2.1 Hz, 1H), 7.90(dt, J=8.4, 2.1 Hz, 1H), 7.40 (dd, J=8.4, 4.9 Hz, 1H), 7.16 (s, 1H),6.00 (s, 1H), 4.50 (s, 2H), 4.09 (s, 2H), 3.19 (br s, 1H), 2.93 (br s,2H), 2.63 (br s, 4H), 1.89 (br s, 4H).

TRV-1472 (0.3402, 1.0 mmol) was dissolved in THF (10 mL) and cooled to−78° C. under argon. nBuLi (0.60 mL, 1.16 mmol, 2.0 M solution incyclohexane) was added dropwise and the resultant dark solution wasstirred for 20 minutes before trifluoro Weinreb amide (0.16 mL, 1.26mmol) was added. The mixture was allowed to stir overnight while warmingto room temperature, it was then cooled to 0° C. and quenched with 2 NHCl (aq), stirring for 60 minutes. This mixture was then made basic withthe dropwise addition of 2 N NaOH (aq) and then extracted with EtOAc.The combined organic layers were then washed with H₂O (3×), brine, dried(MgSO₄), filtered and concentrated. The material was purified via(10-100% EtOAc/hexane gradient and then a 1-10% MeOH/EtOAc gradient with5% TEA additive the whole time) to afford 0.108 g (30% yield) ofTRV-1477 as a mixture of the ketone and hydrated ketone. ¹H NMR (CDCl3,700 MHz) ketone: δ=7.77 (s, 1H), 6.28 (s, 1H), 4.47 (br s, 2H), 4.05 (brs, 2H), 3.13-3.06 (m, 1H), 2.81 (d, J=7.7 Hz, 2H), 2.54 (br s, 4H),1.81-1.78 (m, 4H); hydrated ketone: δ=7.40 (s, 1H), 6.16 (s, 1H),4.43-4.38 (m, 2H), 4.01-3.99 (m, 2H), (remaining peaks are overlappingwith the ketone); ¹H NMR (DMSO, 700 MHz) hydrated ketone: δ=7.85 (s,2H), 7.27 (s, 1H), 6.14 (s, 1H), 4.32 (t, J=8.4 Hz, 2H), 3.88 (t, J=7.0Hz, 2H), 3.03-2.95 (m, 1H), 2.69 (d, J=7.0 Hz, 2H), 2.44-2.43 (m, 4H),1.68-1.66 (m, 4H); ketone: δ=7.83 (s, 1H), 6.25 (s, 1H), 4.42 (br s,2H), 3.99 (br s, 2H), (remaining peaks are overlapping with hydratedketone).

TRV-1472 (0.1584 g, 0.47 mmol) and (3,5-dichlorophenyl)boronic acid(0.0.0941 g, 0.49 mmol) were sealed in a tube. The tube was evacuatedand purged with argon (3 cycles). 2M Na₂CO₃ (0.71 mL, 2.0 M aq solution)was added along with DME (1.1 mL). The solution was degassed for 10minutes and then Pd(PPh₃)₄ (0.0272 g, 0.024 mmol) was added all at once.The tube was re-sealed and heated to 80° C. overnight. After cooling toroom temperature, the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (5% MeOH/DCM) to afford 0.0348 g (18% yield)of TRV-1478. ¹H NMR (DMSO, 500 MHz) δ=7.87 (d, J=2.0 Hz, 2H), 7.69 (t,J=2.0 Hz, 1H), 7.45 (s, 1H), 6.28 (s, 1H), 4.38 (t, J=8.5 Hz, 2H),3.99-3.96 (m, 2H), 3.03-2.94 (m, 1H), 2.71 (d, J=7.5 Hz, 2H), 2.46 (brs, 4H), 1.68 (br s, 4H).

TRV-1472 (0.1987 g, 0.59 mmol) and 3-methylsulfonylphenylboronic acid(0.1240 g, 0.62 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (0.9 mL, 2.0 M aq solution) wasadded along with DME (1.3 mL). The solution was degassed for 10 minutesand then Pd(PPh₃)₄ (0.034 g, 0.03 mmol) was added all at once. The tubewas re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (1-10% MeOH/DCM gradient) to afford 0.1103 g(45% yield) of TRV-1479. ¹H NMR (CDCl3, 500 MHz) δ=8.17 (s, 1H), 7.99(d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.17(s, 1H), 6.01 (s, 1H), 4.51 (t, J=8.5 Hz, 2H), 4.11-4.09 (m, 2H), 3.22(br s, 1H), 3.12 (s, 3H), 2.98 (br s, 2H), 2.75 (br s, 4H), 1.91 (br s,4H).

TRV-1472 (0.2075 g, 0.615 mmol) and 3-acetylbenzeneboronic acid (0.1059g, 0.65 mmol) were sealed in a tube. The tube was evacuated and purgedwith argon (3 cycles). 2M Na₂CO₃ (0.92 mL, 2.0 M aq solution) was addedalong with DME (1.4 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.036 g, 0.031 mmol) was added all at once. The tube wasre-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-10% MeOH/DCM gradient) to afford 0.1307 g(56% yield) of TRV-1480. ¹H NMR (CDCl3, 500 MHz) δ=8.19 (t, J=1.5 Hz,1H), 7.99 (d, J=7.5 Hz, 1H), 7.81 (dd, J=7.5, 1.5 Hz, 1H), 7.57 (t,J=7.5 Hz, 1H), 7.16 (s, 1H), 6.04 (s, 1H), 4.48 (t, J=8.5 Hz, 2H),4.07-4.04 (m, 2H), 3.15 (br s, 1H), 2.90 (br s, 2H), 2.67 (s, 3H), 2.64(br s, 4H), 1.85 (br s, 4H).

TRV-1472 (0.2009 g, 0.60 mmol) and 2-methylsulfonylphenylboronic acid(0.1260 g, 0.63 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (0.9 mL, 2.0 M aq solution) wasadded along with DME (1.3 mL). The solution was degassed for 10 minutesand then Pd(PPh₃)₄ (0.034 g, 0.03 mmol) was added all at once. The tubewas re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-100% EtOAc/hexane gradient with 5% TEA)to afford 0.0257 g (10% yield) of TRV-1481. ¹H NMR (CDCl3, 500 MHz)δ=8.21 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz,1H), 7.39 (d, J=7.5 Hz, 1H), 6.98 (s, 1H), 5.93 (s, 1H), 4.48 (t, J=8.0Hz, 2H), 4.07 (br s, 2H), 3.23 (br s, 1H), 3.05-3.01 (m, 2H), 2.91 (s,3H), 2.77 (br s, 4H), 1.93 (br s, 4H).

TRV-1472 (0.2039 g, 0.60 mmol) and (4-acetylaminophenyl)boronic acid(0.1128 g, 0.63 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (0.9 mL, 2.0 M aq solution) wasadded along with DME (1.3 mL). The solution was degassed for 10 minutesand then Pd(PPh₃)₄ (0.036 g, 0.03 mmol) was added all at once. The tubewas re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-10% MeOH/DCM gradient with 1% TEA) toafford 0.1350 g (57% yield) of TV-1482. ¹H NMR (CDCl3, 500 MHz) δ=7.61(d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.47 (s, 1H), 7.11 (s, 1H),6.04 (s, 1H), 4.46 (t, J=8.0 Hz, 2H), 4.06-4.04 (m, 2H), 3.19 (br s,1H), 3.00 (br s, 2H), 2.77 (br s, 4H), 2.23 (s, 3H), 1.93 (br s, 4H).

TRV-1472 (0.1910 g, 0.57 mmol) and 3,4-dimethoxybenzeneboronic acid(0.1092 g, 0.60 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (0.90 mL, 2.0 M aq solution) wasadded along with DME (1.3 mL). The solution was degassed for 10 minutesand then Pd(PPh₃)₄ (0.034 g, 0.029 mmol) was added all at once. The tubewas re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-8% MeOH/DCM) to afford 0.0471 g (21%yield) of TRV-1483. ¹H NMR (CDCl3, 500 MHz) δ=7.18 (dd, J=8.0, 2.0 Hz,1H), 7.12 (d, J=2.0 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.07(s, 1H), 4.48 (t, J=8.0 Hz, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.96 (s, 3H),3.94 (s, 3H), 3.20 (br s, 1H), 2.98 (br s, 2H), 2.74 (br s, 4H), 1.92(br s, 4H).

TRV-1472 (0.2297 g, 0.68 mmol) and 3-trifluorobenzeneboronic acid(0.1367 g, 0.72 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.0 mL, 2.0 M aq solution) wasadded along with DME (1.5 mL). The solution was degassed for 10 minutesand then Pd(PPh₃)₄ (0.039 g, 0.034 mmol) was added all at once. The tubewas re-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-8% MeOH/DCM) to afford 0.0377 g (14%yield) of TRV-1484. ¹H NMR (CDCl3, 500 MHz) δ=7.84 (s, 1H), 7.78 (d,J=7.5 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.16 (s,1H), 6.02 (s, 1H), 4.51 (t, J=8.0 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.22(br s, 1H), 3.00 (br s, 2H), 2.75 (br s, 4H), 1.92 (br s, 4H).

TRV-1472 (0.2067 g, 0.61 mmol) and benzofuran-2-ylboronic acid (0.1042g, 0.64 mmol) were sealed in a tube. The tube was evacuated and purgedwith argon (3 cycles). 2M Na₂CO₃ (0.92 mL, 2.0 M aq solution) was addedalong with DME (1.4 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.035 g, 0.031 mmol) was added all at once. The tube wasre-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-8% MeOH/DCM) to afford 0.1032 g (45%yield) of TRV-1485. ¹H NMR (CDCl3, 500 MHz) δ=7.62 (d, J=8.0 Hz, 1H),7.56-7.54 (m, 2H), 7.37-7.33 (m, 1H), 7.28-7.25 (m, 1H), 7.15 (s, 1H),6.26 (s, 1H), 4.50 (t, J=8.0 Hz, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.16 (brs, 1H), 2.93 (br s, 2H), 2.67 (br s, 4H), 1.88 (br s, 4H).

TRV-1472 (0.2044 g, 0.61 mmol) and phenylboronic acid (0.0776 g, 0.63mmol) were sealed in a tube. The tube was evacuated and purged withargon (3 cycles). 2M Na₂CO₃ (0.92 mL, 2.0 M aq solution) was added alongwith DME (1.4 mL). The solution was degassed for 10 minutes and thenPd(PPh₃)₄ (0.036 g, 0.031 mmol) was added all at once. The tube wasre-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography (0-8% MeOH/DCM) to afford 0.0702 g (34%yield) of TRV-1486. ¹H NMR (CDCl3, 500 MHz) δ=7.62 (d, J=7.0 Hz, 2H),7.47 (t, J=7.0 Hz, 2H), 7.43 (d, J=7.0 Hz, 1H), 7.16 (s, 1H), 6.08 (s,1H), 4.47 (t, J=8.0 Hz, 2H), 4.06-4.03 (m, 2H), 3.16 (br s, 1H), 2.94(br s, 2H), 2.69 (br s, 4H), 1.88 (br s, 4H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-(tert-butyl)phenyl) boronic acid (139 mg, 0.78 mmol), and Pd(PPh₃)₄(35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 4 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (1:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 200 mg (85% yield) of TRV-1487 as ayellow solid. ¹H NMR (500 MHz, CDCl₃) 1.42 (s, 4H), 1.95 (br, s, 4H),2.76 (br, s, 4H), 3.01 (br, s, 2H), 3.23 (br, s, 1H), 4.08-4.11 (m, 2H),4.52 (t, J=8.2, 2H), 6.16 (s, 1H), 7.21 (s, 1H), 7.55 (d, J=8.4, 2H),7.62 (d, J=8.4, 2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-methoxy-3-methylphenyl) boronic acid (130 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(2:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 190 mg (84% yield) ofTRV-1488 as red oil. ¹H NMR (500 MHz, CDCl3) 1.88 (t, 4H), 2.34 (s, 3H),2.64 (br, s, 4H), 2.90 (d, J=7.4, 2H), 3.13-3.16 (m, 1H), 3.94 (s, 3H),4.05-4.08 (m, 2H), 4.50 (t, J=8.2, 2H), 6.11 (s, 1H), 6.95 (d, J=8.4,1H), 7.14 (s, 1H), 7.46 (s, 1H), 7.49 (d-d, J=8.4, J=2.2, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-isopropylphenyl) boronic acid (128 mg, 0.78 mmol), and Pd(PPh₃)₄ (35mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 4 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (1:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 165 mg (73% yield) of TRV-1489 as ayellow solid. ¹H NMR (500 MHz, CDCl3) 1.35 (d, J=7.0, 6H), 1.88 (t,J=3.1, 4H), 2.63 (br, s, 4H), 2.89 (d, J=7.5, 2H), 3.01-3.05 (m, 1H),3.12-3.18 (m, 1H), 4.05-4.08 (m, 2H), 4.50 (t, J=8.2, 2H), 6.13 (s, 1H),7.19 (s, 1H), 7.38 (d, J=8.2, 2H), 7.60 (d, J=8.2, 2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(3-chloro-4-methylphenyl) boronic acid (133 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(1:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 165 mg (73% yield) ofTRV-1490 as red oil. ¹H NMR (500 MHz, CDCl₃) 1.88 (t, J=3.1, 4H), 2.48(s, 3H), 2.64 (br, s, 4H), 2.90 (d, J=7.4, 2H), 3.15-3.18 (m, 1H),4.06-4.09 (m, 2H), 4.51 (t, J=8.2, 2H), 6.03 (s, 1H), 7.15 (s, 1H), 7.36(d, J=7.9, 1H), 7.45 (d-d, J=7.9, J=1.7, 1H), 7.64 (d, J=1.7, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-phenoxyphenyl) boronic acid (167 mg, 0.78 mmol), and Pd(PPh₃)₄ (35mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 4 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (1:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 215 mg (84% yield) of TRV-1491 as a redsolid. ¹H NMR (500 MHz, CDCl₃) 1.97 (br, s, 4H), 2.80 (br, s, 4H), 3.04(br, s, 2H), 3.5 (br, s, 1H), 4.11-4.13 (m, 2H), 4.54 (t, J=8.2, 2H),6.12 (s, 1H), 7.12-7.14 (m, 4H), 7.18 (s, 1H), 7.21 (t, J=7.5, 1H), 7.44(t, J=7.8, 2H), 7.63 (d, J=8.6, 2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-phenoxyphenyl) boronic acid (145 mg, 0.78 mmol), and Pd(PPh₃)₄ (35mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 4 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 178 mg (74% yield) of TRV-1492 as redoil. ¹H NMR (500 MHz, CDCl₃) 1.98 (br, s, 4H), 2.83 (br, s, 4H), 3.06(s, 2H), 3.27 (br, s, 1H), 4.02 (s, 3H), 4.12-4.14 (m, 2H), 4.4 (t,J=8.2, 2H), 6.06 (s, 1H), 7.06 (d, J=8.6, 1H), 7.15 (s, 1H), 7.55 (d-d,J=8.6, J=2.3, 1H), 7.69 (d, J=2.3, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(3-cyanophenyl) boronic acid (115 mg, 0.78 mmol), and Pd(PPh₃)₄ (35 mg,0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate(2.5 mL, 2M) was added. The reaction mixture was heated to 90° C. for 6h. After completion checked by TLC, 10 mL of water was added, and thereaction mixture was extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate and then concentrated. The residuewas purified via flash column chromatography (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 159 mg (73% yield) of TRV-1493 as a redsolid. ¹H NMR (500 MHz, CDCl₃) 1.87-1.89 (br, s, 4H), 2.63 (br, s, 4H),2.90 (d, J=7.5, 2H), 3.15-3.18 (m, 1H), 4.09-4.12 (m, 2H), 4.53 (t,J=8.3, 2H), 5.97 (s, 1H), 7.15 (s, 1H), 7.63 (t, J=7.8, 1H), 7.74 (d,J=7.7, 1H), 7.88 (d, J=7.9, 1H), 7.93 (s, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-methylnaphthalen-1-yl) boronic acid (145 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(1:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 204 mg (85% yield) ofTRV-1494 as a red solid. ¹H NMR (500 MHz, CDCl₃) 1.85-1.86 (m, 4H), 2.61(br, s, 4H), 2.81 (s, 3H), 2.89 (d, J=7.4, 2H), 3.11-3.14 (m, 1H),4.03-4.06 (m, 2H), 4.45-4.48 (m, 2H), 6.01 (s, 1H), 7.14 (s, 1H), 7.43(s, 2H), 7.52 (t, J=7.3, J=7.9, 1H), 7.62 (t, J=7.7, J=7.4, 1H), 8.01(d, J=7.4, 1H), 8.13 (d, J=7.5, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(2-(trifluoromethoxy) phenyl) boronic acid (161 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(1:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 211 mg (84% yield) ofTRV-1495 as red oil. ¹H NMR (500 MHz, CDCl₃) 2.06 (br, s, 4H), 2.97 (br,s, 4H), 3.19 (br, s, 2H), 3.37 (br, s, 1H), 4.12-4.14 (m, 2H), 4.53-4.56(m, 2H), 6.01 (s, 1H), 7.15 (s, 1H), 7.42-7.46 (m, 2H), 7.49-7.51 (m,2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(6-chloropyridin-3-yl) boronic acid (161 mg, 0.78 mmol), and Pd(PPh₃)₄(35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 4 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (6:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 167 mg (75% yield) of TRV-1496 as redoil. ¹H NMR (500 MHz, CDCl₃) 1.92 (br, s, 4H), 2.17 (br, s, 4H), 2.97(d, J=5.8, 2H), 3.21-3.22 (m, 1H), 4.13 (br, s, 2H), 4.53-4.54 (m, 2H),5.97 (s, 1H), 7.16 (s, 1H), 7.49 (d, J=8.1, 1H), 7.92 (d, J=7.8, 1H),8.69 (s, 1H).

A solution of 3-azeditinecarboxylic acid (3.4889 g, 34.5 mmol) in water(60 mL) was cooled in an ice bath and DIPEA (18 mL, 103.5 mmol) wasadded. The mixture was stirred for 5 minutes and then a solution of6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole 3 (7.4877 g, 34.5 mmol) in THF(60 mL) was added dropwise. The reaction was stirred for 30 minutes at0° C., then it was removed from the ice bath and allowed to warm to roomtemperature overnight. The reaction was diluted with water and thenbasified with 2N NaOH (aq). The aqueous layer was then washed with DCM(3×) and then acidified with 2N HCl(aq). The resulting precipitate wascollected by filtration to afford 4.8909 grams (48% yield) of a finebrown solid. A mixture of this material, pyrrolidine (1.36 mL, 16.4mmol) and TEA (5.7 mL, 41 mmol) in THF (140 mL) was cooled in an icebath. The solution of T3P (12.54 g, 19.7 mmol, 50 w/w solution in EtOAc)was added dropwise and then the reaction was allowed to warm to roomtemperature. The reaction was then diluted with water and extracted withEtOAc (3×). The combined organic layers were then washed with water(3×), brine, dried (MgSO₄), filtered and concentrated to afford 3.4558 g(60% yield, <95% c.p.). 85 mg of this material was purified via 3%MeOH/DCM column. This afforded approximately 60 mg (71% recovery) of afine orange solid of TRV-1497. ¹H NMR (500 MHz, DMSO) δ=7.40 (s, 1H),6.10 (s, 1H), 4.45 (t, J=8.5 Hz, 2H), 4.35 (t, J=8.5 Hz, 2H), 3.86-3.81(m, 1H), 3.35-3.30 (m, 4H), 1.90-1.85 (m, 2H), 1.81-1.75 (m, 2H).

TRV-1497 (0.4031 g, 1.15 mmol) and 3-formylbezeneboronic acid (0.1810 g,1.21 mmol) were added to a tube and the tube was evacuated and purgedwith argon (3×). DME (2.8 mL) and Na₂CO₃ (1.7 mL, 3.4 mmol, 2 N aqueoussolution) were added followed by Pd(PPh₃)₄ (0.069 g, 0.06 mmol). Thetube was sealed and then heated to 85° C. overnight. The reaction wascooled and then diluted with EtOAc and water. The organic layer waswashed with water (3×), brine, dried (MgSO₄), filtered and concentratedto give the crude aldehyde. This aldehyde was dissolved in THF (10 mL)and cooled in an ice bath. CF₃TMS (0.19 mL) was added and then thecatalyst TBAF (0.1 mL, 1.0 M solution) was added. After 30 minutes thereaction was removed from the ice bath and allowed to warm to roomtemperature. Once complete by TLC, recooled to 0° C. and 2 N HCl(aq) wasadded, stirred for 40 minutes and then basified with 2N NaOH. Thismixture was extracted with EtOAc. The combined extracts were washed withwater (2×), brine, filtered and concentrated. The crude material waspurified via chromatography (5% MeOH/DCM) to afford 0.261 g (51% yield)of TRV-1498 as an orange solid. ¹H NMR (500 MHz, DMSO) δ=7.91 (s, 1H),783 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H),7.35 (s, 1H), 6.93 (d, J=5.5 Hz, 1H), 6.32 (s, 1H), 5.32-5.26 (m, 1H),4.51-4.49 (m, 2H), 4.40 (t, J=7.0 Hz, 2H), 3.92-3.86 (m, 1H), 3.39 (t,J=6.5 Hz, 2H), 3.35 (t, J=6.5 Hz, 2H), 1.94-1.88 (m, 2H), 1.84-1.78 (m,2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(2-(hydroxymethyl) phenyl) boronic acid (119 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 3 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(6:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 142 mg (64% yield) ofTRV-1499 as red oil. ¹H NMR (400 MHz, CDCl₃) 1.78-1.81 (m, 4H),1.83-1.87 (m, 1H), 2.51-2.55 (m, 4H), 2.81 (d, J=7.5, 2H), 3.02-3.09 (m,1H), 3.97-4.01 (m, 2H), 4.42 (t, J=8.3, 2H), 4.67 (s, 2H), 5.84 (s, 1H),6.95 (s, 1H), 7.32 (d-d, J=7.6, J=1.5, 1H), 7.38 (t-d, J=7.5, J=1.5,1H), 7.45 (t-d, J=7.4, J=1.7, 1H), 7.59 (d, J=8.0, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(2,3-dimethoxyphenyl) boronic acid (142 mg, 0.78 mmol), and Pd(PPh₃)₄(35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 2 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 141 mg (72% yield) of TRV-1500 as redoil. ¹H NMR (400 MHz, CDCl₃) 1.79-1.82 (m, 4H), 2.52-2.55 (m, 4H), 2.81(d, J=7.5, 2H), 3.02-3.09 (m, 1H), 3.68 (s, 3H), 3.94 (s, 3H), 3.96-4.00(m, 2H), 4.42 (t, J=8.3, 2H), 6.08 (s, 1H), 6.98-7.00 (m, 2H), 7.11-7.16(m, 2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-(methylsulfonyl)phenyl) boronic acid (156 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(4:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 163 mg (66% yield) ofTRV-1501 as a red solid. ¹H NMR (400 MHz, CDCl₃) 1.79-1.83 (m, 4H),2.53-2.57 (m, 4H), 2.83 (d, J=7.6, 2H), 3.09-3.13 (m, 1H), 4.04-4.08 (m,2H), 4.49 (t, J=8.4, 2H), 5.98 (s, 1H), 7.16 (s, 1H), 7.81 (d, J=8.0,2H), 8.05 (d, J=8.3, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-(trifluoromethyl)phenyl) boronic acid (148 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(1:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 205 mg (85% yield) ofTRV-1502 as a yellow solid. ¹H NMR (400 MHz, CDCl₃) 1.80-1.83 (m, 4H),2.53-2.57 (m, 4H), 2.83 (d, J=7.5, 2H), 3.07-3.13 (m, 1H), 4.03-4.07 (m,2H), 4.48 (t, J=8.3, 2H), 6.00 (s, 1H), 7.16 (s, 1H), 7.73 (s, 4H).

LDA (6 ml, 12 mmol, 2 M solution in THF) was added dropwise to a stirredsolution of 1-Boc-4-piperidone (1.99 g, 10 mmol) in THF (30 mL) at −78°C. under nitrogen atmosphere. After 20 minutes, a THF solution (10 ml)of N-phenyl-bis(trifluomethanesulfonimide) was added to the mixture at−78° C., and the viscous light yellow solution was stirred overnight andthe temperature was allowed to warm to RT. The mixture was added 30 mlof hexanes and washed with brine. The organic layer was dried andconcentrated.

tert-Butyl4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(2.02 g, 61%) was obtained via chromatography (5:95 EtOAc/Hexane).

A round-bottomed flask was charged with tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(2.02 g, 6.1 mmol), bis(pinacolato)diboron (2.32 g, 9.15 mmol),Potassium acetate (1.79 g, 18.3 mmol), and PdCl₂(dppf) (223 mg, 0.31mmol). After degassed, dioxane (15 mL) was added. The reaction mixturewas heated to 90° C. for 2 h. After the reaction was completed, themixture was cooled to rt. 40 mL of EtOAc was added, and the reactionmixture was washed with water for 3 times. The organic phase was driedover anhydrous sodium sulphate and then concentrated. The residue waspurified by flash chromatography (1:10 EtOAc/Hexane). 1.55 g (82%) oftert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylatewas obtained as a solid.

A round-bottomed flask was charged with TRV-1472 (1.422 g, 4.22 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.500 g, 4.85 mmol), and Pd(PPh₃)₄ (195 mg, 0.169 mmol). Afterdegassed, dioxane (12 mL) and aqueous sodium carbonate (6 mL, 2M) wasadded. The reaction mixture was heated to 90° C. for 2.5 h. Aftercompletion checked by TLC, 50 mL of water was added, and the reactionmixture was extracted with ethyl acetate. The organic phase was driedover anhydrous sodium sulphate and then concentrated. The residue waspurified via flash column chromatography (1:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 1.80 g (97% yield) of tert-butyl4-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

tert-butyl4-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.80 g, 4.09 mmol) was stirred in the solution of DCM/CF₃COOH (2:1, 21ml) for 1 hour at 0° C. After completion checked by TLC, the mixture wascarefully neutralized with saturated K₂CO3 solution until no more gasgave out at 0° C. 50 ml of DCM was added to the solution and mixture waswashed with water. The organic layer was dried over anhydrous sodiumsulphate and then concentrated. The crude(4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[c][1,2,5]oxadiazole)was used for the next step without further purification.

TEA (3.06 ml, 22 mmol) and acetic anhydride (1.04 ml, 11 mmol) wereadded dropwise to a solution of crude(4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[c][1,2,5]oxadiazole)(250 mg, 0.735 mmol) in THF (10 ml) at rt respectively. The mixture wasstirred for 3 hours. After completion checked by TLC, the reaction wasquenched by Hexanes/H₂O (1:1, 50 ml). The mixture was washed with 2 NNaOH and brine. The organic layer was dried and concentrated. Theresidue was purified via chromatography (6:5:100:500MeOH/TEA/EtOAc/Hexane) to afford TRV-1503 (210 mg 75%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) 1.77-1.84 (m, 4H), 2.16 (s, 1.28H), 2.19(s, 1.72H), 2.51-2.56 (m, 4H), 2.57-2.64 (m, 2H), 2.80 (d, J=7.5, 2H),3.03-3.10 (m, 1H), 3.69 (t, J=5.6, 0.85H), 3.83 (t, J=5.8, 1.15H),3.96-4.00 (m, 2H), 4.17 (d, J=3.0, 0.85H), 4.28 (d, J=2.4, 1.15H), 4.42(t, J=7.7, 2H), 5.87 (s, 0.43H), 5.90 (s, 0.57H), 6.15 (s, 0.43H), 6.24(s, 0.57H), 6.90 (s, 0.57H), 6.94 (s, 0.43H).

A reaction vial was charged with TRV 1472 (0.19 g, 0.56 mmol),(2-phenoxyphenyl)boronic acid (0.14 g, 0.67 mmol), and Pd(PPh₃)₄ (0.032g, 0.028 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (5 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (2%of triethylamine and 2% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.20 g (84% yield) of TRV 1504 as a redsolid. ¹H NMR (CDCl₃, 400 MHz) δ=7.52 (dt, J₁=1.51 Hz, J₂=7.53 Hz, 1H),7.38 (dt, J₁=1.75 Hz, J₂=7.80 Hz, 1H), 7.30 (t, J=8.54 Hz, 2H), 7.24 (t,J=7.53 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J=7.40 Hz, 2H), 6.95 (d, J=7.53Hz, 2H), 6.03 (s, 1H), 4.32 (t, J=8.16 Hz, 2H), 3.87 (dd, J₁=6.12 Hz,J₂=8.03 Hz, 2H), 3.01 (septet, J=7.28 Hz, 1H), 2.76 (d, J=7.28 Hz, 2H),2.56-2.46 (m, 4H), 1.85-1.75 (m, 4H).

A reaction vial was charged with TRV 1472 (0.16 g, 0.48 mmol),(3-chlorophenyl)boronic acid (0.10 g, 0.64 mmol), and Pd(PPh₃)₄ (0.028g, 0.024 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (5 mL) and aq. sodium carbonate (3 mL, 2.0 M, 6.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (2%of triethylamine and 2% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.15 g (85% yield) of TRV 1505 as red oil.¹H NMR (CDCl₃, 400 MHz) δ=7.60 (s, 1H), 7.52-7.48 (m, 1H), 7.43-7.38 (m,2H), 7.13 (s, 1H), 6.99 (s, 1H), 4.48 (t, J=8.29 Hz, 2H), 4.04 (dd,J₁=5.90 Hz, J₂=8.66 Hz, 2H), 3.10 (septet, J=6.97 Hz, 1H), 2.82 (d,J=7.28 Hz, 2H), 2.59-2.51 (m, 4H), 1.86-1.78 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(3,5-dimethylphenyl)boronic acid (0.15 g, 1.00 mmol), and Pd(PPh₃)₄(0.086 g, 0.074 mmol). The vial was degassed and refilled with nitrogen.To the vial was added dioxane (5 mL) and aq. sodium carbonate (2 mL, 2.0M, 4.0 mmol). The reaction was re-degassed, refilled with nitrogen, andthen heated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (5%of triethylamine and 1.5% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.20 g (75% yield) of TRV 1506 as a yellowsolid. ¹H NMR (CDCl₃, 400 MHz) δ=7.24 (s, 2H), 7.14 (d, J=0.75 Hz, 1H),7.07 (s, 1H), 6.07 (s, 1H), 4.46 (t, J=8.28 Hz, 2H), 4.02 (dd, J₁=5.65Hz, J₂=8.41 Hz, 2H), 3.09 (septet, J=7.66 Hz, 1H), 2.82 (d, J=7.53 Hz,2H), 2.59-2.51 (m, 4H), 2.41 (s, 6H), 1.86-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(4-propylphenyl)boronic acid (0.16 g, 1.00 mmol), and Pd(PPh₃)₄ (0.086g, 0.074 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (5%of triethylamine and 1.5% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.25 g (90% yield) of TRV 1507 as a yellowsolid. ¹H NMR (CDCl₃, 400 MHz) δ=7.55 (d, J=8.28 Hz, 2H), 7.29 (d,J=8.28 Hz, 2H), 7.15 (d, J=0.75 Hz, 1H), 6.08 (s, 1H), 4.46 (t, J=8.88Hz, 2H), 4.02 (dd, J₁=5.65 Hz, J₂=8.41 Hz, 2H), 3.08 (septet, J=6.78 Hz,1H), 2.82 (d, J=7.28 Hz, 2H), 2.66 (t, J=7.66 Hz, 2H), 2.59-2.50 (m,4H), 1.87-1.78 (m, 4H), 1.70 (sextet, J=7.28 Hz, 2H), 0.99 (t, J=7.28Hz, 3H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),thiophen-3-ylboronic acid (0.13 g, 1.00 mmol), and Pd(PPh₃)₄ (0.043 g,0.037 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (5%of triethylamine and 1% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.20 g (79% yield) of TRV 1509 as an orangesolid. ¹H NMR (CDCl₃, 400 MHz) δ=7.58 (t, J=2.13 Hz, 1H), 7.43 (d,J=2.01 Hz, 2H), 7.19 (s, 1H), 6.09 (s, 1H), 4.46 (t, J=8.41 Hz, 2H),4.03 (dd, J₁=5.90 Hz, J₂=8.46 Hz, 2H), 3.09 (septet, J=6.59 Hz, 1H),2.82 (d, J=7.53 Hz, 2H), 2.62-2.48 (m, 4H), 1.89-1.76 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),furan-3-ylboronic acid (0.15 g, 1.30 mmol), and Pd(PPh₃)₄ (0.043 g,0.037 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (5%of triethylamine and 1% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.18 g (75% yield) of TRV 1510 as an orangesolid. ¹H NMR (CDCl₃, 400 MHz) δ=7.81 (s, 1H), 7.52 (t, J=1.63 Hz, 1H),7.08 (s, 1H), 6.75 (t, J=0.87 Hz, 1H), 5.94 (s, 1H), 4.45 (t, J=8.28 Hz,2H), 4.01 (dd, J₁=5.77 Hz, J₂=8.54 Hz, 2H), 3.08 (septet, J=6.72 Hz,1H), 2.81 (d, J=7.53 Hz, 2H), 2.59-2.51 (m, 4H), 1.87-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(2,6-dimethoxyphenyl)boronic acid (0.18 g, 1.00 mmol), and Pd(PPh₃)₄(0.043 g, 0.037 mmol). The vial was degassed and refilled with nitrogen.To the vial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0M, 4.0 mmol). The reaction was re-degassed, refilled with nitrogen, andthen heated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography (5%of triethylamine and 1% of methanol in a 5:1 mixture solvent of hexaneand ethyl acetate) to afford 0.21 g (72% yield) of TRV 1511 as a yellowsolid. ¹H NMR (CDCl₃, 400 MHz) δ=7.33 (t, J=8.26 Hz, 1H), 6.99 (s, 1H),6.68 (d, J=8.28 Hz, 1H), 5.82 (s, 1H), 4.39 (t, J=8.16 Hz, 2H), 3.96(dd, J₁=5.65 Hz, J₂=8.41 Hz, 2H), 3.77 (s, 6H), 3.04 (septet, J=6.65 Hz,1H), 2.79 (d, J=7.53 Hz, 2H), 2.58-2.48 (m, 4H), 1.85-1.75 (m, 4H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(4-acetylphenyl) boronic acid (128 mg, 0.78 mmol), and Pd(PPh₃)₄ (35 mg,0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate(2.5 mL, 2M) was added. The reaction mixture was heated to 90° C. for 4h. After completion checked by TLC, 10 mL of water was added, and thereaction mixture was extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate and then concentrated. The residuewas purified via flash column chromatography (3:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 199 mg (88% yield) of TRV-1512 as a redsolid. ¹H NMR (400 MHz, CDCl₃) 1.80-1.83 (m, 4H), 2.53-2.56 (m, 4H),2.67 (s, 3H), 2.82 (d, J=7.5, 2H), 3.07-3.13 (m, 1H), 4.03-4.07 (m, 2H),4.48 (t, J=8.3, 2H), 6.03 (s, 1H), 7.19 (d, J=1.0, 1H), 7.70-7.73 (m,2H), 8.04-8.07 (m, 2H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(2-(trifluoromethyl)phenyl) boronic acid (148 mg, 0.78 mmol), andPd(PPh₃)₄ (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueoussodium carbonate (2.5 mL, 2M) was added. The reaction mixture was heatedto 90° C. for 4 h. After completion checked by TLC, 10 mL of water wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulphate and thenconcentrated. The residue was purified via flash column chromatography(1:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 190 mg (79% yield) ofTRV-1514 as orange oil. ¹H NMR (400 MHz, CDCl₃) 1.78-1.82 (m, 4H),2.52-2.55 (m, 4H), 2.81 (d, J=7.3, 2H), 3.03-3.10 (m, 1H), 3.98-4.02 (m,2H), 4.42 (t, J=8.3, 2H), 5.77 (s, 1H), 6.93 (s, 1H), 7.39 (d, J=7.8,1H), 7.52 (t, J=7.4, 1H), 7.60 (t, J=7.5, 1H), 7.77 (d, J=7.5, 1H).

A round-bottomed flask was charged with TRV-1472 (202 mg, 0.6 mmol),(2,4-dimethoxyphenyl) boronic acid (142 mg, 0.78 mmol), and Pd(PPh₃)₄(35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodiumcarbonate (2.5 mL, 2M) was added. The reaction mixture was heated to 90°C. for 2 h. After completion checked by TLC, 10 mL of water was added,and the reaction mixture was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulphate and then concentrated.The residue was purified via flash column chromatography (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 190 mg (61% yield) of TRV-1515 as ayellow solid. ¹H NMR (400 MHz, CDCl₃): 1.78-1.82 (m, 4H), 2.55 (s, br,4H), 2.81 (d, J=7.3, 2H), 3.02-3.09 (m, 1H), 3.84 (s, 3H), 3.88 (s, 3H),3.95-3.99 (m, 2H), 4.41 (t, J=8.2, 2H), 6.04 (s, 1H), 6.58-6.60 (m, 2H),7.09 (s, 1H), 7.30-7.32 (m, 1H).

A round-bottomed flask was charged with TRV-1472 (250 mg, 0.742 mmol),(4-(dimethylcarbamoyl)phenyl) boronic acid (172 mg, 0.89 mmol), andPd(PPh₃)₄ (43 mg, 0.037 mmol). After degassed, dioxane (5 mL) andaqueous sodium carbonate (2.5 mL, 2M) was added. The reaction mixturewas heated to 90° C. for 2.5 h. After completion checked by TLC, 10 mLof water was added, and the reaction mixture was extracted with ethylacetate. The organic phase was dried over anhydrous sodium sulphate andthen concentrated. The residue was purified via flash columnchromatography (5:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford 207 mg (85%yield) of TRV-1516 as a red solid. ¹H NMR (400 MHz, CDCl₃): 1.80-1.84(m, 4H), 2.54-2.56 (m, 4H), 2.82 (d, J=7.3, 2H), 3.05 (s, 3H), 3.07-3.13(m, 1H), 3.16 (s, 3H), 4.02-4.06 (m, 2H), 4.47 (t, J=8.2, 2H), 6.03 (s,1H), 7.15 (s, 1H), 7.27 (s, 1H), 7.53 (d, J=8.3, 1H), 7.66 (d, J=8.3,2H).

TEA (2.05 ml, 14.7 mmol) and methyl iodide (0.46 ml, 7.35 mmol) wereadded dropwise to a solution of crude(4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[c][1,2,5]oxadiazole)(250 mg, 0.735 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 5 hours. The reaction was quenched by EtOAc/H₂O (1:1, 50ml). The mixture was washed with 2 N NaOH and brine. The organic layerwas dried and concentrated. The residue was purified via chromatography(7:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford Compound TRV-1517 (120 mg,46%) as red oil. ¹H NMR (400 MHz, CDCl₃): 1.79-1.83 (m, 4H), 2.43 (s,3H), 2.52-2.55 (m, 4H), 2.58-2.63 (m, 2H), 2.67-2.71 (m, 2H), 2.79 (d,J=7.5, 2H), 3.02-3.09 (m, 1H), 3.13-3.17 (m, 2H), 3.94-3.98 (m, 2H),4.40 (t, J=8.2, 2H), 5.95 (s, 1H), 6.22 (t, J=3.6, 1H), 6.95 (s, 1H).

TEA (0.41 ml, 2.94 mmol) and Methanesulfonyl chloride (0.11 ml, 1.47mmol) were added dropwise to a solution of crude(4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[c][1,2,5]oxadiazole)(250 mg, 0.735 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 5 hours. The reaction was quenched by EtOAc/H₂O (1:1, 50ml). The mixture was washed with 2 N NaOH and brine. The organic layerwas dried and concentrated. The residue was purified via chromatography(5:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford Compound TRV-1518 (250 mg,81%) as red solid. ¹H NMR (400 MHz, CDCl3): 1.80-1.82 (m, 4H), 2.52-2.57(m, 4H), 2.66-2.71 (m, 2H), 2.80 (d, J=7.3, 2H), 2.89 (s, 3H), 3.04-3.11(m, 1H), 3.54 (t, J=5.6, 2H), 3.97-4.01 (m, 4H), 4.42 (t, J=8.2, 2H),5.80 (s, 1H), 6.21 (s, br, 1H), 6.93 (s, 1H).

Potassium carbonate (203 mg, 1.47 mmol) and 2-bromo-ethyl methyl ether(0.316 ml, 3.3 mmol) were added dropwise to a solution of crude(4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[c][1,2,5]oxadiazole)(250 mg, 0.735 mmol) in acetonitrile (10 ml) at rt respectively. Themixture was stirred for overnight. The reaction was quenched byEtOAc/H₂O (1:1, 50 ml). The mixture was washed with 2 N NaOH and brine.The organic layer was dried and concentrated. The residue was purifiedvia chromatography (5:5:100:500 MeOH/TEA/EtOAc/Hexane) to affordCompound TRV-1519 (180 mg, 61%) as red oil. ¹H NMR (400 MHz, CDCl3):1.78-1.82 (m, 4H), 2.52-2.55 (m, 4H), 2.60 (s, br, 2H), 2.73 (d, J=5.6,2H), 2.77-2.80 (m, 4H), 3.02-3.08 (m, 1H), 3.26-3.29 (m, 2H), 3.58 (s,3H), 3.60 (t, J=5.6, 2H), 3.94-3.97 (m, 2H), 4.40 (t, J=8.2, 2H), 5.95(s, 1H), 6.21 (t, J=4.0, 1H), 6.93 (s, 1H).

To a flame-dried 2-neck flask was added TRV-1472 (0.2336 g, 0.69 mmol).The flask was evacuated and purged with argon (3×). THF (9.2 mL) wasadded and the solution was cooled to −78° C. nBuLi (0.52 mL, 1.6 Msolution in hexane) was added over 5 minutes, and the reaction wasstirred for an additional 15 minutes. Neat DMF (0.08 mL) was then added,stirred at −78° C. for 60 minutes. At this point, MeOH (1 mL) was addedat −78° C. and the reaction was allowed to warm to room temperature. Themixture was diluted with water and EtOAc and the layers separated. Theaqueous layer was back-extracted with EtOAc (3×). The combined organiclayers were washed with water, brine, dried with MgSO₄, filtered andconcentrated. The crude aldehyde was then dissolved in THF (10 mL) andcooled in an ice bath. CF₃TMS (0.20 mL, 1.38 mmol) was added followed byTBAF (70 μL). the reaction was stirred at 0° C. for 5 minutes and thenwarmed to room temperature. The reaction was complete after 90 minutes.Quenched with 10 mL of 2 N HCl, then diluted with EtOAc and water. Thelayers were separated and the aqueous layer was back-extracted withEtOAc (3×). The combined organic layers were washed with water, brine,dried with MgSO₄, filtered and concentrated. The crude material waspurified with 10% MeOH/DCM column to afford 0.0525 g (21% yield) ofTRV-1520. ¹H NMR (500 MHz, DMSO) δ=7.22 (s, 1H), 7.04 (d, J=6 Hz, 1H),6.06 (s, 1H), 5.23-5.18 (m, 1H), 4.33 (t, J=8 Hz, 2H), 3.91 (t, J=8 Hz,2H), 3.02-2.97 (m, 1H), 2.76 (br s, 2H), 2.49-2.48 (m, 4H, overlappingwith DMSO signal), 1.69 (s, 4H).

LDA (18 ml, 23 mmol, 2 M solution in THF) was added dropwise to astirred solution of 1-Boc-3-piperidone (5.97 g, 30 mmol) in THF (80 mL)at −78° C. under nitrogen atmosphere. After 20 minutes, a THF solution(30 ml) of N-phenyl-bis(trifluomethanesulfonimide) was added to themixture at −78° C., and the viscous light yellow solution was stirredovernight and the temperature was allowed to warm to RT. After additionof saturated NH₄Cl (80 ml), the mixture was diluted with water (100 ml).The mixture was added 150 ml of EtOAc and washed with brine. The organiclayer was dried and concentrated. tert-Butyl5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate(4.02 g, 40.5%) and tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(2.5 g, 25.2%) were obtained via chromatography (5:95 EtOAc/Hexane).

A round-bottomed flask was charged with tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(2.5 g, 7.55 mmol), bis(pinacolato)diboron (2.88 g, 11.33 mmol),Potassium acetate (2.22 g, 22.7 mmol), and PdCl₂(dppf) (276 mg, 0.38mmol). After degassed, dioxane (40 mL) was added. The reaction mixturewas heated to 90° C. for 3 h. After the reaction was completed, themixture was cooled to rt. 40 mL of EtOAc was added, and the reactionmixture was washed with water for 3 times. The organic phase was driedover anhydrous sodium sulphate and then concentrated. The residue waspurified by flash chromatography (1:8:12 EtOAc/DCM/Hexane). 1.5 g(64.3%) of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylatewas obtained as a solid.

A round-bottomed flask was charged with TRV-1472 (1.36 g, 4.05 mmol),tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 4.85 mmol), and Pd(PPh₃)₄ (280 mg, 0.24 mmol).After degassed, dioxane (16 mL) and aqueous sodium carbonate (8 mL, 2M)were added. The reaction mixture was heated to 90° C. for 3 h. Aftercompletion checked by TLC, 20 mL of water was added, and the reactionmixture was extracted with ethyl acetate. The organic phase was driedover anhydrous sodium sulphate and then concentrated. The residue waspurified by flash chromatography (1:5:100:500 MeOH/TEA/EtOAc/Hexane) toafford tert-butyl5-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.7 g, 94.4%).

tert-Butyl5-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.7 g, 3.86 mmol) was stirred in the solution of DCM/CF₃COOH (2:1, 21ml) for 1 hour at 0° C. After completion checked by TLC, the mixture wascarefully neutralized with saturated K₂CO₃ solution until no more gasgave out at 0° C. 15 ml of NaOH (2N) was added to the solution, andextracted with of DCM (3×30 ml). The organic layer was dried overanhydrous sodium sulphate and then concentrated. The crude4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazolewas used for the next step without further purification.

TEA (1.02 ml, 7.35 mmol) and acetic anhydride (0.341 ml, 3.62 mmol) wereadded dropwise to a solution of crude4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazole(250 mg, 0.735 mmol) in THF (10 ml) at rt respectively. The mixture wasstirred for 3 hours. After completion checked by TLC, the reaction wasquenched by Hexane/H₂O (1:1, 50 ml). The mixture was washed with 2 NNaOH and brine. The organic layer was dried and concentrated. Theresidue was purified via chromatography (6:5:100:500MeOH/TEA/EtOAc/Hexane) to afford TRV-1521 (230 mg 82%) as a yellowsolid. ¹H NMR (400 MHz, CDCl3): 1.81 (s, br, 4H), 2.19 (s, 3H),2.36-2.43 (m, 2H), 2.54 (s, br, 4H), 2.79-2.81 (m, 2H), 3.03-3.10 (m,1H), 3.61 (t, J=5.8, 1.2H), 3.77 (t, J=5.8, 0.8H), 3.96-4.02 (m, 2H),4.31-4.47 (m, 4H), 5.87 (s, 1H), 6.32-6.34 (m, 0.6H), 6.42-6.44 (m,0.4H), 6.87 (s, 0.4H), 6.97 (s, 0.6H).

TEA (0.41 ml, 2.94 mmol) and Methanesulfonyl chloride (0.11 ml, 1.47mmol) were added dropwise to a solution of crude4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazole(250 mg, 0.735 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 5 hours. The reaction was quenched by EtOAc/H₂O (1:1, 50ml). The mixture was washed with 2 N NaOH and brine. The organic layerwas dried and concentrated. The residue was purified via chromatography(6:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford Compound TRV-1522 (240 mg,78%) as a red solid. ¹H NMR (400 MHz, CDCl3): 1.79-1.83 (m, 4H),2.48-2.55 (m, 6H), 2.80 (d, J=7.3, 2H), 2.90 (s, 3H), 3.04-3.11 (m, 1H),3.47 (t, J=5.8, 2H), 3.97-4.01 (m, 2H), 4.14-4.16 (m, 2H), 4.43 (t,J=8.2, 2H), 5.83 (s, 1H), 6.35-6.37 (m, 1H), 6.89 (s, 1H).

Potassium carbonate (507 mg, 3.68 mmol) and 2-bromo-ethyl methyl ether(0.316 ml, 3.3 mmol) were added dropwise to a solution of crude4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazole(250 mg, 0.735 mmol) in acetonitrile (10 ml) at rt respectively. Themixture was stirred for overnight. The reaction was quenched byEtOAc/H₂O (1:1, 50 ml). The mixture was washed with 2 N NaOH and brine.The organic layer was dried and concentrated. The residue was purifiedvia chromatography chromatography (4:5:100:500 MeOH/TEA/EtOAc/Hexane) toafford Compound TRV-1523 (210 mg, 72%) as red oil. ¹H NMR (400 MHz,CDCl3):_1.80-1.82 (m, 4H), 2.41-2.42 (m, 2H), 2.54 (s, br, 2H), 2.71 (d,J=5.6, 2H), 2.77-2.81 (m, 4H), 3.02-3.08 (m, 1H), 3.40-3.41 (m, 5H),3.62 (t, J=5.6, 2H), 3.94-3.98 (m, 2H), 4.40 (t, J=8.0, 2H), 5.91 (s,1H), 6.28 (s, br, 1H), 6.87 (s, 1H).

TEA (1.23 ml, 8.82 mmol) and methyl iodide (0.11 ml, 1.76 mmol) wereadded dropwise to a solution of crude4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,2,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazole(300 mg, 0.882 mmol) in DCM (10 ml) at rt respectively. After themixture was stirred for 2 hours, methyl iodide (0.11 ml, 1.76 mmol) wasadded to a solution, and the mixture was stirred for another 3 h. Thereaction was quenched by EtOAc/H₂O (1:1, 50 ml). The mixture was washedwith 2 N NaOH and brine. The organic layer was dried and concentrated.The residue was purified via chromatography (4:5:100:500,MeOH/TEA/EtOAc/Hexane) to afford Compound TRV-1524 (150 mg, 48%) as redoil. ¹H NMR (400 MHz, CDCl₃): 1.81-1.86 (m, 4H), 2.42-2.45 (m, 2H), 2.49(s, 3H), 2.58-2.62 (m, 6H), 2.82 (d, J=7.3, 2H), 3.04-3.11 (m, 1H),3.29-3.31 (m, 2H), 3.95-3.99 (m, 2H), 4.41 (t, J=8.2, 2H), 5.92 (s, 1H),6.28-6.30 (m, 1H), 6.88 (s, 1H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(1H-pyrazol-3-yl)boronic acid (0.10 g, 0.90 mmol), and Pd(PPh₃)₄ (0.043g, 0.037 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography usinggradient elution (TEA:MeOH:hexane:EtOAc 5:3:75:15 toTEA:MeOH:hexane:EtOAc 5:8:75:15) to afford 0.050 g (21% yield) of TRV1525 as a red solid. ¹H NMR (DMSO, 400 MHz) δ=13.11 (broad, 1H), 8.43(broad, 1H), 8.13 (broad, 1H), 7.31 (s, 1H), 6.32 (s, 1H), 4.34 (t,J=8.29 Hz, 2H), 3.92 (dd, J₁=5.53 Hz, J₂=8.54 Hz, 2H), 2.98 (septet,J=6.86 Hz, 1H), 2.71 (d, J=7.53 Hz, 2H), 2.53-2.37 (m, 4H), 1.76-1.62(m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g,0.90 mmol), and Pd(PPh₃)₄ (0.043 g, 0.037 mmol). The vial was degassedand refilled with nitrogen. To the vial was added dioxane (4 mL) and aq.sodium carbonate (2 mL, 2.0 M, 4.0 mmol). The reaction was re-degassed,refilled with nitrogen, and then heated to 90° C. until the reaction wascomplete. The mixture was diluted with water, added 3 mL of 2N NaOH, andextracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (TEA:MeOH:hexane:EtOAc5:3:75:15 to TEA:MeOH:hexane:EtOAc 5:10:75:15) to afford 0.080 g (33%yield) of TRV 1526 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.66 (d,J=2.51 Hz, 1H), 7.35 (s, 1H), 6.73 (d, J=2.26 Hz, 1H), 6.46 (s, 1H),4.46 (t, J=8.28 Hz, 2H), 4.02 (dd, J₁=5.77 Hz, J₂=8.53 Hz, 2H), 3.08(septet, J=6.99 Hz, 1H), 2.81 (d, J=7.28 Hz, 2H), 2.61-2.51 (m, 4H),1.87-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g,0.90 mmol), and Pd(PPh₃)₄ (0.043 g, 0.037 mmol). The vial was degassedand refilled with nitrogen. To the vial was added dioxane (4 mL) and aq.sodium carbonate (2 mL, 2.0 M, 4.0 mmol). The reaction was re-degassed,refilled with nitrogen, and then heated to 90° C. until the reaction wascomplete. The mixture was diluted with water, added 3 mL of 2N NaOH, andextracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (TEA:MeOH:hexane:EtOAc5:3:75:15 to TEA:MeOH:hexane:EtOAc 5:8:75:15) to afford 0.25 g (100%yield) of TRV 1527 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.81 (d,J=0.75 Hz, 1H), 7.70 (s, 1H), 7.05 (d, J=1.00 Hz, 1H), 5.95 (s, 1H),4.44 (t, J=8.29 Hz, 2H), 4.01 (dd, J₁=5.65 Hz, J₂=8.66 Hz, 2H), 3.98 (s,3H), 3.08 (septet, J=7.03 Hz, 1H), 2.81 (d, J=7.53 Hz, 2H), 2.62-2.49(m, 4H), 1.88-1.76 (m, 4H).

A reaction vial was charged with TRV 1472 (0.32 g, 0.95 mmol),pyridin-4-ylboronic acid (0.15 g, 1.20 mmol), and Pd(PPh₃)₄ (0.055 g,0.048 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 1:1:15:3) to afford 0.26 g (82% yield) of TRV1528 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.71 (dd, J₁=1.64 Hz,J₂=6.27 Hz, 1H), 7.52 (dd, J₁=1.26 Hz, J₂=6.27 Hz, 1H), 7.21 (s, 1H),5.99 (s, 1H), 4.49 (t, J=8.28 Hz, 2H), 4.06 (dd, J₁=5.66 Hz, J₂=8.66 Hz,2H), 3.10 (septet, J=6.99 Hz, 1H), 2.82 (d, J=7.53 Hz, 2H), 2.60-2.50(m, 4H), 1.87-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),thiophen-2-ylboronic acid (0.13 g, 1.00 mmol), and Pd(PPh₃)₄ (0.043 g,0.037 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 5:1.2:75:15) to afford 0.21 g (83% yield) of TRV1529 as a brown solid. δ=7.54 (dd, J₁=1.13 Hz, J₂=3.64 Hz, 1H), 7.38(dd, J₁=1.13 Hz, J₂=5.15 Hz, 1H), 7.22 (d, J=1.00 Hz, 1H), 7.13 (dd,J₁=3.64 Hz, J₂=5.15 Hz, 1H), 6.10 (d, J=1.00 Hz, 1H), 4.47 (t, J=8.28Hz, 2H), 4.03 (dd, J₁=5.65 Hz, J₂=8.66 Hz, 2H), 3.09 (septet, J=6.90 Hz,1H), 2.82 (d, J=7.53 Hz, 2H), 2.60-2.53 (m, 4H), 1.87-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),furan-2-ylboronic acid (0.11 g, 1.00 mmol), and Pd(PPh₃)₄ (0.043 g,0.037 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 5:1.2:75:15) to afford 0.18 g (75% yield) of TRV1530 as an orange solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.54 (dd, J₁=0.75 Hz,J₂=1.76 Hz, 1H), 7.31 (s, 1H), 7.29 (dd, J₁=0.75 Hz, J₂=3.76 Hz, 1H),6.53 (J₁=1.76 Hz, J₂=3.51 Hz, 1H), 6.13 (s, 1H), 4.45 (t, J=8.28 Hz,2H), 4.02 (dd, J₁=5.77 Hz, J₂=8.53 Hz, 2H), 3.08 (septet, J=6.99 Hz,1H), 2.81 (d, J=7.53 Hz, 2H), 2.61-2.49 (m, 4H), 1.88-1.76 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(3-(dimethylcarbamoyl)phenyl)boronic acid (0.18 g, 0.91 mmol), andPd(PPh₃)₄ (0.043 g, 0.037 mmol). The vial was degassed and refilled withnitrogen. To the vial was added dioxane (4 mL) and aq. sodium carbonate(2 mL, 2.0 M, 4.0 mmol). The reaction was re-degassed, refilled withnitrogen, and then heated to 90° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate and concentrated. The residue was purified by flashchromatography (TEA:MeOH:hexane:EtOAc:DCM 5:4:60:20:20) to afford 0.24 g(80% yield) of TRV 1531 as a yellow solid. ¹H NMR (CDCl₃, 400 MHz)δ=7.69-7.65 (m, 2H), 7.51 (dt, J₁=1.25 Hz, J₂=7.78 Hz, 1H), 7.46 (dt,J₁=1.25 Hz, J₂=7.53 Hz, 1H), 7.15 (s, 1H), 6.04 (s, 1H), 4.47 (t, J=8.28Hz, 2H), 4.03 (dd, J₁=5.77 Hz, J₂=8.53 Hz, 2H), 3.16 (s, 3H), 3.09(septet, J=6.78 Hz, 1H), 3.04 (s, 3H), 2.81 (d, J=7.53 Hz, 2H),2.59-2.51 (m, 4H), 1.86-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(2-(methylthio)phenyl)boronic acid (0.11 g, 1.00 mmol), and Pd(PPh₃)₄(0.043 g, 0.037 mmol). The vial was degassed and refilled with nitrogen.To the vial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0M, 4.0 mmol). The reaction was re-degassed, refilled with nitrogen, andthen heated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 5:1:75:15) to afford 0.20 g (71% yield) of TRV1532 as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.39 (dt, J₁=2.01 Hz,J₂=7.66 Hz, 1H), 7.31 (d, J=7.78 Hz, 1H), 7.27 (dt, J₁=2.01 Hz, J₂=7.53Hz, 1H), 7.23 (dt, J₁=1.00 Hz, J₂=7.03 Hz, 1H), 7.00 (s, 1H), 5.91 (s,1H), 4.44 (t, J=8.29 Hz, 2H), 4.01 (dd, J₁=5.78 Hz, J₂=8.79 Hz, 2H),3.06 (septet, J=6.78 Hz, 1H), 2.82 (d, J=7.53 Hz, 2H), 2.59-2.49 (m,4H), 2.43 (s, 3H), 1.63-1.53 (m, 4H).

A round-bottomed flask was charged with tert-butyl5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate(4.02 g, 12.15 mmol), bis(pinacolato)diboron (4.63 g, 18.22 mmol),potassium acetate (3.57 g, 36.44 mmol), and PdCl₂(dppf) (445 mg, 0.61mmol). After degassed, dioxane (60 mL) was added. The reaction mixturewas heated to 90° C. for 3 h. After the reaction was completed, themixture was cooled to rt. 40 mL of EtOAc was added, and the reactionmixture was washed with water for 3 times. The organic phase was driedover anhydrous sodium sulphate and then concentrated. The residue waspurified by flash chromatography (1:19, EtOAc/Hexane). 2.27 g (60.5%) oftert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate was obtained as a solid.

A round-bottomed flask was charged with TRV-1472 (2.06 g, 6.12 mmol),tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (2.27 g, 7.35 mmol), and Pd(PPh₃)₄ (354 mg, 0.306mmol). After degassed, dioxane (16 mL) and aqueous sodium carbonate (8mL, 2M) were added. The reaction mixture was heated to 90° C. for 3 h.After completion checked by TLC, 20 mL of water was added, and thereaction mixture was extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate and then concentrated. The residuewas purified by flash chromatography to afford tert-butyl5-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (2.65 g, 98.4%). ¹H NMR (400 MHz, CDCl₃): 1.55 (s, 9H),1.79-1.83 (m, 4H), 1.96-2.02 (m, 2H), 2.47 (t, J=5.9, 2H), 2.54 (s, br,4H), 2.78-2.82 (m, 2H), 3.02-3.09 (m, 1H), 3.63 (s, br, 2H), 3.94-3.97(m, 2H), 4.40 (t, J=8.2, 2H), 5.90 (s, 0.44H), 6.03 (s, 0.6H), 6.86 (s,1H), 7.43 (s, 0.4H), 7.66 (s, 0.6H).

tert-Butyl5-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate(440 g, 1.0 mmol) was stirred in the solution of DCM/CF₃COOH (2:1, 6 ml)for 6 hour at 0° C. After completion checked by TLC, the mixture wascarefully neutralized with saturated K₂CO₃ solution until no more gasgave out at 0° C. 15 ml of NaOH (2N) was added to the solution, andextracted with of DCM (3×10 ml). The organic layer was dried overanhydrous sodium sulphate and then concentrated. The crude4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,4,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazolewas used for the next step without further purification.

TEA (1.39 ml, 10 mmol) and acetic anhydride (0.471 ml, 5 mmol) wereadded dropwise to a solution of4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,4,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazole(crude, 1 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 3 hours. After completion checked by TLC, the reaction wasquenched by EtOAc/H₂O (1:1, 50 ml). The mixture was washed with 2 N NaOHand brine. The organic layer was dried and concentrated. The residue waspurified via gradient elution (5:100:500, TEA/EtOAc/Hexane to3:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford TRV-1533 (65 mg, 17%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃): 1.79-1.83 (m, 4H), 1.96-2.02 (m,1.1H), 2.04-2.10 (m, 0.9H), 2.26 (s, 1.35H), 2.31 (s, 1.65H), 2.50-2.55(m, m, 6H), 2.79-2.82 (m, 2H), 3.02-3.11 (m, 1H), 3.66-3.69 (m, 0.9H),3.76-3.78 (m, 1.1H), 3.96-4.01 (m, 2H), 4.42 (t, J=8.2, 2H), 5.84 (s,0.55H), 6.02 (s, 0.45H), 6.90-6.91 (m, 1H), 7.15 (s, 0.55H), 7.93 (s,0.45H).

TEA (0.7 ml, 5 mmol) and Methanesulfonyl chloride (0.39 ml, 5 mmol) wereadded dropwise to a solution of4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(1,4,5,6-tetrahydropyridin-3-yl)benzo[c][1,2,5]oxadiazole(crude, 1 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 3 hours. The reaction was quenched by EtOAc/H₂O (1:1, 50ml). The mixture was washed with 2 N NaOH and brine. The organic layerwas dried and concentrated. The residue was purified via gradientelution (5:100:500, TEA/EtOAc/Hexane to 2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford TRV-1534 (105 mg, 25%) as a red solid.¹H NMR (400 MHz, CDCl₃): 1.80-1.83 (m, 4H), 2.06-2.12 (m, 2H), 2.50-2.55(m, 6H), 2.79 (d, J=7.5, 2H), 2.97 (s, 3H), 3.03-3.09 (m, 1H), 3.64 (t,J=5.5, 2H), 3.96-4.00 (m, 2H), 4.42 (t, J=8.2, 2H), 5.87 (s, 1H), 6.87(s, 1H), 7.19 (s, 1H).

TRV-1472 (0.4 g, 1.15 mmol) and 2-formylthiophene-4-boronic acid (0.188g, 1.21 mmol) were added to a tube and the tube was evacuated and purgedwith argon (3×). DME (2.8 mL) and Na₂CO₃ (1.7 mL, 3.4 mmol, 2 N aqueoussolution) were added followed by Pd (PPh₃)₄ (0.069 g, 0.06 mmol). Thetube was sealed and then heated to 85° C. overnight. The reaction wascooled and then diluted with EtOAc and water. The organic layer waswashed with water (3×), brine, dried (MgSO₄), filtered and concentratedto give the crude aldehyde. Aldehyde was purified using columnchromatography and was used in next step directly. Aldehyde4-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)thiophene-2-carbaldehydewas dissolved in THF (10 mL) and cooled in an ice bath. CF₃TMS (0.19 mL)was added and then the catalyst TBAF (0.1 mL, 1.0 M solution) was added.After 30 minutes the reaction was removed from the ice bath and allowedto warm to room temperature. Once complete by TLC, recooled to 0° C. and2 N HCl (aq) was added, stirred for 40 minutes and then basified with 2NNaOH. This mixture was extracted with EtOAc. The combined extracts werewashed with water (2×), brine, filtered and concentrated. The crudematerial was purified via chromatography(hexane:ethylacetate:triethylamine:methanol, 5:1:0.3:0.1) to afford0.210 mg (58%) of TRV 1535 as yellow solid. ¹H NMR (500 MHz, CDCl3) δ7.59 (d, J=3.6 Hz, 1H), 7.49 (s, 1H), 7.13 (d, J=3.6 Hz, 1H), 5.97 (s,1H), 5.32-5.28 (m, 1H), 4.44-4.39 (m, 2H), 4.02-3.98 (m, 2H), 3.09-3.03(m, 1H), 2.81-2.83 (d, J=8 Hz, 2H), 2.58 (m, 4H), 1.85 (m, 4H).

A reaction vial was charged with TRV 1472 (0.67 g, 2.00 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.50 g, 2.40 mmol), and Pd(PPh₃)₄ (0.12 g, 0.10 mmol). The vial wasdegassed and refilled with nitrogen. To the vial was added dioxane (6mL) and aq. sodium carbonate (3 mL, 2.0 M, 6.0 mmol). The reaction wasre-degassed, refilled with nitrogen, and then heated to 90° C. until thereaction was complete. The mixture was diluted with water, added 3 mL of2N NaOH, and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:hexane:EtOAc 5:1:75:15 to TEA:MeOH:hexane:EtOAc 5:5:75:15) toafford 0.67 g (99% yield) of TRV 1536 as a red solid. ¹H NMR (CDCl₃, 400MHz) δ=7.55 (d, J=2.00 Hz, 2H), 7.01 (d, J=0.76 Hz, 1H), 6.40 (d, J=2.01Hz, 2H), 5.82 (s, 1H), 4.46 (t, J=8.29 Hz, 2H), 4.03 (dd, J₁=5.40 Hz,J₂=8.67 Hz, 2H), 3.97 (s, 3H), 3.09 (septet, J=7.09 Hz, 1H), 2.82 (d,J=7.53 Hz, 2H), 2.60-2.49 (m, 4H), 1.87-1.76 (m, 4H).

A solution of6-bromo-4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(0.38 g, 1.13 mmol) in 6 mL of anhydrous THF was cooled to −78° C. undernitrogen. To the solution was added n-butyllithium (0.55 mL, 2.5 M, 1.38mmol) dropwise. After complete addition, the reaction mixture wasstirred for 30 minutes at the same temperature, and then tributyltinchloride (0.46 mL, 1.70 mmol) was added. The reaction was stirred for 1h at −78° C. before quenched with methanol. The mixture was diluted withbrine, extracted with ethyl acetate. The ethyl acetate phase was driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby flash chromatography using gradient elution (TEA:hexane:EtOAc 2:100:0to TEA:hexane:EtOAc 2:95:5) to afford 0.48 g (77% yield) of4-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tri-n-butylstannyl)benzo[c][1,2,5]oxadiazoleas deep orange oil. ¹H NMR (CDCl₃, 400 MHz) δ=7.14 (s, 1H), 5.89 (s,1H), 4.40 (t, J=8.03 Hz, 2H), 3.96 (dd, J₁=5.77 Hz, J₂=8.28 Hz, 2H),3.06 (septet, J=7.53 Hz, 1H), 2.81 (d, J=7.53 Hz, 2H), 2.61-2.49 (m,4H), 1.88-1.76 (m, 4H), 1.61-1.51 (m, 6H), 1.35 (sextet, J=7.28 Hz, 6H),1.09 (t, J=8.09 Hz, 6H), 0.91 (t, J=7.28 Hz, 9H).

A reaction vial was charged with4-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tri-n-butylstannyl)benzo[c][1,2,5]oxadiazole(0.33 g, 0.60 mmol), 1-(4-bromothiophen-2-yl)-2,2,2-trifluoroethan-1-ol(0.16 g, 0.60 mmol), Pd(PPh₃)₄ (0.035 g, 0.030 mmol), Cul (0.011 g, 0.06mmol), and CsF (0.18 g, 1.20 mmol). The vial was degassed and refilledwith nitrogen. To the vial was added DMF (4 mL). The reaction wasre-degassed, refilled with nitrogen, sealed, and then heated to 50° C.until the reaction was complete. The mixture was diluted with water,added 3 mL of 2N NaOH, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(TEA:MeOH:hexane:EtOAc 5:1:75:15 to TEA:MeOH:hexane:EtOAc 5:5:75:15) toafford 0.080 g (31% yield) of TRV 1537 as a red solid. ¹H NMR (CDCl₃,400 MHz) δ=8.23 (d, J=1.51 Hz, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.34 (d,J=5.52 Hz, 1H), 6.35 (s, 1H), 5.50 (pentet, J=6.52 Hz, 1H), 4.37 (t,J=8.03 Hz, 2H), 3.96 (dd, J₁=6.02 Hz, J₂=8.28 Hz, 2H), 2.99 (septet,J=7.53 Hz, 1H), 2.71 (d, J=7.53 Hz, 2H), 2.48-2.41 (m, 4H), 1.73-1.63(m, 4H).

TRV-1472 (2.0095 g, 5.96 mmol) was dissolved in THF (60 mL) and cooledto −78° C. nBuLi (4.5 mL, 1.6 M solution in hexane) was added dropwiseover 10 minutes and stirred for an additional 10 minutes. CO₂ gas wasbubbled through the reaction mixture via canula while gradually warmingto room temperature. The reaction was then concentrated to give 2.12grams of a dark solid. This material was then dissolved in NMP (70 mL)and then 20 mL aliquots of this mixture were used in the HATU couplingstep. The lithium carboxylate 1 in NMP (20 mL, 0.6068 g of 1) was cooledto 0° C. and DIPEA (1.0 mL, 5.91 mmol) was added; followed by HATU(0.8239 g, 2.16 mmol). This mixture was stirred for 5 minutes beforeadding morpholine (0.52 mL, 5.91 mmol) and the reaction was stirreduntil complete by TLC. The reaction was diluted with brine and extractedwith DCM (3×). The combined layers were dried with MgSO₄, filtered andconcentrated. The crude residue was purified via chromatography, thefirst attempt was with 10% MeOH/DCM which failed to give >95% chemicalpurity. The purification was repeated with EtOAc:Hexane:TEA (6:4:0.5) toafford 0.0803 g (11% yield) of TRV-1538 as a waxy solid. ¹H NMR (500MHz, DMSO) δ=7.06 (s, 1H), 5.88 (s, 1H), 4.34 (t, J=5 Hz, 2H), 3.92 (t,J=5 Hz, 2H), 3.65 (br s, 2H), 3.60 (br s, 2H), 3.54 (br s, 2H), 3.35 (brs, 2H), 3.03-2.95 (m, 1H), 2.70 (d, J=10 Hz, 2H), 2.44 (br s, 4H), 1.67(br s, 4H).

TRV-1520 (0.3249 g, 0.91 mmol) was dissolved in NMP (10 mL) and wascooled in an ice bath. NaH (0.0401 g, 1.00 mmol, 60% in mineral oil) wasadded portion-wise and stirred for 20 minutes, after which time,iodomethane (0.056 mL, 0.91 mmol) was added to the reaction and themixture was stirred overnight. The reaction was recooled to 0° C. andquenched with saturated ammonium chloride. The mixture was extractedwith DCM (3×) and the combined organic layers were dried with MgSO₄,filtered and concentrated. The crude residue was purified via 8%MeOH/DCM and then again with EtOAC/Hexane/TEA (6:4:0.5) to afford 0.0602g (18% yield) of TRV-1539. ¹H NMR (500 MHz, DMSO) δ=7.20 (s, 1H), 5.93(s, 1H), 5.10 (q, J=7 Hz, 1H), 4.36-4.32 (m, 2H), 3.93-3.89 (m, 2H),3.39 (s, 3H), 3.01-2.96 (m, 1H), 2.71 (d, J=5 Hz, 2H), 2.44 (br s, 4H),1.70-1.64 (m, 4H).

TRV-1472 (2.0095 g, 5.96 mmol) was dissolved in THF (60 mL) and cooledto −78° C. nBuLi (4.5 mL, 1.6 M solution in hexane) was added dropwiseover 10 minutes and stirred for an additional 10 minutes. CO₂ gas wasbubbled through the reaction mixture via canula while gradually warmingto room temperature. The reaction was then concentrated to give 2.12grams of a dark solid. This material was then dissolved in NMP (70 mL)and then 20 mL aliquots of this mixture were used in the HATU couplingstep. The lithium carboxylate 1 in NMP (20 mL, 0.6068 g of 1) was cooledto 0° C. and DIPEA (1.0 mL, 5.91 mmol) was added; followed by HATU(0.8239 g, 2.16 mmol). This mixture was stirred for 5 minutes beforeadding diethylamine (1.0 mL, 5.91 mmol) and the reaction was stirreduntil complete by TLC. The reaction was diluted with brine and extractedwith DCM (3×). The combined layers were dried with MgSO₄, filtered andconcentrated. The crude residue was purified via chromatography, thefirst attempt was with EtOAc:Hexane:TEA (6:4:0.5) which failed togive >95% chemical purity. The purification was repeated with 10%MeOH/DCM to afford 0.0823 g (12% yield) of TRV-1540 as a waxy solid. ¹HNMR (500 MHz, DMSO) δ=6.99 (s, 1H), 5.81 (s, 1H), 4.35 (t, J=10 Hz, 2H),3.93 (t, J=10 Hz, 2H), 3.42 (d, J=10 Hz, 2H), 3.21 (d, J=10 Hz, 2H),3.00-2.97 (m, 1H), 2.72 (br s, 2H), 2.46 (br s, 4H), 1.68 (br s, 4H),1.19-1.13 (m, 3H), 1.10-1.03 (m, 3H).

TRV-1472 (2.0095 g, 5.96 mmol) was dissolved in THF (60 mL) and cooledto −78° C. nBuLi (4.5 mL, 1.6 M solution in hexane) was added dropwiseover 10 minutes and stirred for an additional 10 minutes. CO₂ gas wasbubbled through the reaction mixture via canula while gradually warmingto room temperature. The reaction was then concentrated to give 2.12grams of a dark solid. This material was then dissolved in NMP (70 mL)and then 20 mL aliquots of this mixture were used in the HATU couplingstep. The lithium carboxylate 1 in NMP (20 mL, 0.6068 g of 1) was cooledto 0° C. and DIPEA (1.0 mL, 5.91 mmol) was added; followed by HATU(0.8239 g, 2.16 mmol). This mixture was stirred for 5 minutes beforeadding cyclopropylamine (0.41 mL, 5.91 mmol) and the reaction wasstirred until complete by TLC. The reaction was diluted with brine andextracted with DCM (3×). The combined layers were dried with MgSO₄,filtered and concentrated. The crude residue was purified viachromatography, the first attempt was with EtOAc:Hexane:TEA (6:4:0.5)which failed to give >95% chemical purity. The purification was repeatedwith 10% MeOH/DCM to afford 0.0459 g (6.8% yield) of TRV-1541 as a waxysolid. ¹H NMR (500 MHz, DMSO) δ=8.57 (d, J=5 Hz, 1H), 7.47 (s, 1H), 6.29(s, 1H), 4.35 (t, J=10 Hz, 2H), 3.93 (t, J=10 Hz, 2H), 3.01-2.96 (m,1H), 2.86-2.81 (m, 1H), 2.71 (d, J=10 Hz, 2H), 2.45 (br s, 4H), 1.68 (brs, 4H), 0.72-0.69 (m, 2H), 0.59-0.56 (m, 2H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(2-(dimethylcarbamoyl)phenyl)boronic acid (0.18 g, 0.91 mmol), andPd(PPh₃)₄ (0.043 g, 0.037 mmol). The vial was degassed and refilled withnitrogen. To the vial was added dioxane (4 mL) and aq. sodium carbonate(2 mL, 2.0 M, 4.0 mmol). The reaction was re-degassed, refilled withnitrogen, and then heated to 90° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate and concentrated. The residue was purified by flashchromatography (TEA:MeOH:hexane:EtOAc 5:3:75:15) to afford 0.23 g (77%yield) of TRV 1542 as red oil. ¹H NMR (CDCl₃, 400 MHz) δ=7.52-7.38 (m,4H), 7.02 (s, 1H), 5.98 (s, 1H), 4.42 (t, J=8.28 Hz, 2H), 3.99 (dd,J₁=5.65 Hz, J₂=8.41 Hz, 2H), 3.06 (septet, J=7.03 Hz, 1H), 2.94 (s, 3H),2.79 (d, J=7.53 Hz, 2H), 2.65 (s, 3H), 2.58-2.46 (m, 4H), 1.86-1.72 (m,4H).

TRV-1472 (0.4 g, 1.15 mmol) and 5-formylthiophene-2-boronic acid (0.188g, 1.21 mmol) were added to a tube and the tube was evacuated and purgedwith argon (3×). DME (2.8 mL) and Na₂CO₃ (1.7 mL, 3.4 mmol, 2 N aqueoussolution) were added followed by Pd (PPh₃)₄ (0.069 g, 0.06 mmol). Thetube was sealed and then heated to 80° C. overnight. The reaction wascooled and then diluted with EtOAc and water. The organic layer waswashed with water (3×), brine, dried (MgSO₄), filtered and concentratedto give the crude aldehyde. Aldehyde was purified using columnchromatography and was used in next step directly. Aldehyde 2 wasdissolved in THF (5 mL) and cooled in an ice bath. CF₃TMS (0.19 mL) wasadded and then the catalyst TBAF (0.1 mL, 1.0 M solution) was added.After 30 minutes the reaction was removed from the ice bath and allowedto warm to room temperature. Once complete by TLC, recooled to 0° C. and2 N HCl (aq) was added, stirred for 40 minutes and then basified with 2NNaOH. This mixture was extracted with EtOAc. The combined extracts werewashed with water (2×), brine, filtered and concentrated. The crudematerial was purified via chromatography (hexane:ethylacetate:triethylamine:methanol, 5:1:0.3:0.1) to afford 40 mg (28%) ofTRV 1543 as yellow solid. ¹H NMR (400 MHz, CDCl3) δ 7.33 (d, J=3.6 Hz,1H), 7.20-7.20 (m, 2H), 5.99 (s, 1H), 5.31-5.25 (m, 1H), 4.45-4.40 (m,2H), 4.02-3.99 (m, 2H), 3.09-3.03 (m, 1H), 2.83-2.81 (d, J=8 Hz, 2H),2.57 (m, 4H), 1.83 (m, 4H).

4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tributylstannyl)benzo[c][1,2,5]oxadiazole(0.4 g, 0.73 mmol), 1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-ol(0.230 g, 0.9 mmol), CsF (0.45 g, 2.19 mmol), CuI (14 mg, 0.073 mmol),Pd(PPh3)4, (0.042 g, 0.0365 mmol) was charged in glass tube and sealed,it was then degassed and flushed with N₂. DMF (10 ml) was added andreaction mixture was heated at 45° C. overnight. After completion ofreaction by TLC, the reaction was cooled and then diluted with EtOAc andwater. The organic layer was washed with water (3×), brine, dried(MgSO₄), filtered and concentrated to give the crude product which waspurified using column chromatography to give TRV-1544 (0.120 g, 42%). ¹HNMR (400 MHz, DMSO): δ 9.03 (d, J=3.6 Hz, 1H), 8.75 (s, 1H), 8.26 (s,1H), 7.41 (s, 1H), 7.19 (d, J=4.0 Hz, 1H), 6.26 (s, 1H), 5.37-5.45 (m,1H), 4.40 (m, 2H), 3.99 (m, 2H), 2.97-3.04 (m, 1H), 2.72 (d, J=8.0 Hz,2H), 2.45 (s, 4H), 1.68 (s, 4H).

4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tributylstannyl)benzo[c][1,2,5]oxadiazole(0.4 g, 0.73 mmol), 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-ol(0.230 g, 0.9 mmol), CsF (0.45 g, 2.19 mmol), CuI (14 mg, 0.073 mmol),Pd(PPh3)4, (0.042 g, 0.0365 mmol) was charged in glass tube and sealed,it was then degassed and flushed with N2. DMF (10 ml) was added andreaction mixture was heated at 45° C. overnight. After completion ofreaction by TLC, the reaction was cooled and then diluted with EtOAc andwater. The organic layer was washed with water (3×), brine, dried(MgSO₄), filtered and concentrated to give the crude product which waspurified using column chromatography to give TRV-1545 (0.108 g, 36%). ¹HNMR (400 MHz, DMSO): δ 8.80 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.03 (d,J=8.0 Hz, 1H), 7.80 (s, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 5.40 (m, 1H),4.39 (m, 2H), 3.96 (m, 2H), 3.0 (m, 1H), 2.72 (d, J=4.0 Hz, 2H), 2.45(s, 4H), 1.68 (s, 4H).

A reaction vial was charged with4-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tri-n-butylstannyl)benzo[c][1,2,5]oxadiazole(0.33 g, 0.60 mmol), 1-(4-bromothiophen-2-yl)-2,2,2-trifluoroethan-1-ol(0.16 g, 0.60 mmol), Pd(PPh₃)₄ (0.035 g, 0.030 mmol), Cul (0.011 g, 0.06mmol), and CsF (0.18 g, 1.20 mmol). The vial was degassed and refilledwith nitrogen. To the vial was added DMF (4 mL). The reaction wasre-degassed, refilled with nitrogen, sealed, and then heated to 50° C.until the reaction was complete. The mixture was diluted with water,added 3 mL of 2N NaOH, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(TEA:MeOH:hexane:EtOAc 5:1:75:15 to TEA:MeOH:hexane:EtOAc 5:5:75:15) toafford 0.14 g (42% yield) of2-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)thiazole-5-carbaldehydeas a yellow solid.

2-(7-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)thiazole-5-carbaldehyde(0.14 g, 0.38 mmol) was dissolved in THF (5 mL) and cooled to 0° C.CF₃TMS (0.085 mL, 0.57 mmol) was added followed by TBAF (0.050 mL, 1.0 Msolution in THF, 0.050 mmol). The reaction was then stirred for 60minutes before re-cooling to 0° C. and 4N HCl (aq) was added and stirredfor 60 minutes, and then basified with 3N aq. NaOH and extracted withEtOAc. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography usinggradient elution (TEA:MeOH:hexane:EtOAc 5:1:75:15 toTEA:MeOH:hexane:EtOAc 5:5:75:15) to afford 0.090 g (54% yield) of TRV1546 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.54 (s, 1H), 7.48 (s,1H), 6.42 (s, 1H), 5.20 (q, J=6.53 Hz, 1H), 4.49 (t, J=8.28 Hz, 2H),4.30 (broad, 1H), 4.11-4.03 (m, 2H), 3.10 (septet, J=7.19 Hz, 1H), 2.82(d, J=7.28 Hz, 2H), 2.60-2.50 (m, 4H), 1.87-1.77 (m, 4H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(4-fluorophenyl)boronic acid (0.14 g, 1.00 mmol), and Pd(PPh₃)₄ (0.043g, 0.037 mmol). The vial was degassed and refilled with nitrogen. To thevial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0 M, 4.0mmol). The reaction was re-degassed, refilled with nitrogen, and thenheated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 5:1:75:15) to afford 0.20 g (77% yield) of TRV1547 as red oil. ¹H NMR (CDCl₃, 400 MHz) δ=7.63-7.56 (m, 2H), 7.20-7.13(m, 2H), 7.10 (s, 1H), 6.00 (s, 1H), 4.47 (t, J=8.28 Hz, 2H), 4.03 (dd,J₁=5.77 Hz, J₂=8.53 Hz, 2H), 3.09 (septet, J=6.65 Hz, 1H), 2.82 (d,J=7.53 Hz, 2H), 2.60-2.50 (m, 4H), 1.86-1.77 (m, 4H).

Methyl7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carboxylate(0.2146 g, 0.68 mmol) was dissolved in methanol (2 mL) and 7N NH₃ inmethanol (12 mL) was added to the tube. The tube was sealed and heatedto 50° C. for 48 hours behind a blast shield. The mixture was thenconcentrated to afford the crude amide. The crude amide was purified viachromatography (10% MeOH/DCM with NH₄OH layer) to produce 0.1439 g (70%yield) of TRV-1548 ¹H NMR (500 MHz, DMSO) δ=8.10 (s, 1H), 7.58 (s, 1H),7.57 (s, 1H), 6.36 (s, 1H), 4.35 (t, J=10 Hz, 2H), 3.92 (q, J=5 Hz, 2H),3.02-2.94 (m, 1H), 2.70 (d, J=10 Hz, 2H), 2.44 (br s, 4H), 1.68-1.65 (m,4H).

TRV-1551 (0.1830 g, 0.54 mmol) was dissolved in DCM (10 mL) and cooledto 0° C. TEA (0.75 mL, 5.4 mmol) was added followed by the dropwiseaddition of MeSO₂Cl (0.21 mL, 2.7 mmol). The reaction was allowed towarm to room temperature and stirred until complete by TLC. The reactionwas then concentrated and the residue was made basic by the addition of2N NaOH(aq). This basic residue was then extracted with DCM (3×). Thecombined organic layers were washed with water, brine, dried (MgSO₄),filtered and concentrated to afford the crude amide. The material waspurified via chromatography EtOAC:hexane:TEA (9:1:0.5) to afford 0.1417g (63% yield) of TRV-1549. ¹H NMR (500 MHz, CDCl3) δ=6.98 (s, 1H), 5.95(s, 1H), 5.17 (q, J=10 Hz, 1H), 4.39 (q, J=10 Hz, 2H), 3.99-3.95 (m,2H), 3.05 (br s, 1H), 2.97 (s, 3H), 2.81 (br s, 2H), 2.54 (br s, 4H),2.30-2.26 (m, 1H), 1.81 (br s, 4H), 1.73 (d, J=10 Hz, 3H), 1.02-0.96 (m,1H), 0.81-0.75 (m, 1H), 0.57-0.52 (m, 2H).

TRV-1551 (0.2133 g, 0.62 mmol) was dissolved in DCM (10 mL) and cooledto 0° C. TEA (0.86 mL, 6.2 mmol) was added followed by the dropwiseaddition of AcCl (0.22 mL, 3.1 mmol). The reaction was allowed to warmto room temperature and stirred until complete by TLC. The reaction wasthen concentrated and the residue was made basic by the addition of 2NNaOH(aq). This basic residue was then extracted with DCM (3×). Thecombined organic layers were washed with water, brine, dried (MgSO₄),filtered and concentrated to afford the crude amide. The material waspurified via chromatography EtOAC:hexane:TEA (9:1:0.5) to afford 0.1858g (78% yield) of TRV-1550. ¹H NMR (500 MHz, CDCl3) δ=6.87 (s, 1H), 5.70(s, 1H), 5.68-5.67 (m, 1H), 4.37 (t, J=10 Hz, 1H), 4.32 (t, J=10 Hz,1H), 3.95-3.89 (m, 2H), 3.05-2.97 (m, 1H), 2.78-2.73 (m, 2H), 2.56-2.52(m, 5H), 2031 (s, 3H), 1.79 (s, 4H), 1.67 (d, J=10 Hz, 3H), 0.82-0.75(m, 1H), 0.69-0.60 (m, 3H).

TRV-1472 (1.7789 g, 5.28 mmol) was dissolved in toluene (25 mL) in atube and Tributyl(1-ethoxyvinyl)tin (2.4789 g, 6.86 mmol) were added.The solution was degassed for 10 minutes by bubbling argon through thesolution. Pd(PPh₃)₄ (0.6125 g, 0.53 mmol) was then added, the tube wassealed and the mixture was heated at 110° C. for 16 hours. An aliquotfor ¹H NMR indicated the reaction had reached 100% conversion. Thematerial was filtered through Celite and then concentrated. The residuewas dissolved in DCM and washed with aqueous KF solution, resulting in aprecipitate. This material was removed by filtration. The organic layerwas then washed with water, brine, dried (MgSO₄), filtered andconcentrated. The crude material was partially dissolved in THF (80 mL)and EtOH (6 mL) was added to achieve complete solution. The solution wasthen cooled to 0° C. and 2N HCl(aq) (11 mL) was added dropwise. Stirredat 0° C. for 5 minutes before removing the ice bath. Stirred untilcomplete by TLC (60 minutes) and then concentrated to remove the THF.The residue was cooled to 0° C. and then made basic with 2N NaOH (aq).This basic mixture was extracted with DCM (3×) and the combined organicswere washed with water, brine, dried (MgSO₄), filtered and concentratedto afford the crude ketone 8. This ketone was then dissolved in methanol(50 mL) and cyclopropyl amine (0.76 mL, 11 mmol) and Ti(OiPr)₄ (2.1 mL,6.9 mmol) were added producing a brown precipitate. This mixture wasthen cooled in an ice bath and NaBH₄ (0.2989 g, 7.9 mmol) was addedportionwise and then stirred until complete by TLC. The reaction wasthen quenched with the addition of NH₄Cl and then diluted with EtOAc.The layers were separated and the aqueous layer was back-extracted withEtOAc. The combined organic layers were washed with water, brine, dried(MgSO₄) filtered and concentrated. The crude amine was purified viachromatography (10% MeOH/DCM) to afford 0.8689 g (48% yield fromTRV-1472) of TRV-1551. ¹H NMR (500 MHz, DMSO) δ=6.99 (s, 1H), 6.09 (s,1H), 4.29 (t, J=10 Hz, 2H), 3.86 (t, J=10 Hz, 2H), 3.73 (s, 1H),3.00-2.91 (m, 1H), 2.75 (s, 1H), 2.69 (d, J=10 Hz, 2H), 2.44 (s, 4H),1.88-1.84 (m, 1H), 1.70-1.64 (m, 4H), 1.23 (d, J=5 Hz, 3H), 0.29-0.19(m, 4H).

TRV-1472 (0.7014 g, 2.08 mmol) was dissolved in THF (20 mL) and cooledto −78° C. nBuLi (1.8 mL, 1.6 M solution in hexane) was added dropwiseover 10 minutes and stirred for an additional 10 minutes. CO₂ gas wasbubbled through the reaction mixture via cannula while gradually warmingto room temperature. The reaction was then concentrated to give 800 mgof a dark solid. This material was then dissolved in NMP (30 mL) andthen 15 mL aliquots of this mixture were used in the HATU coupling step.The lithium carboxylate 1 in NMP (15 mL, 1.04 mmol of 1) was cooled to0° C. and DIPEA (0.54 mL, 3.12 mmol) was added; followed by HATU (0.4349g, 1.14 mmol). This mixture was stirred for 5 minutes before addingpiperidine (0.31 mL, 3.13 mmol) and the reaction was stirred untilcomplete by TLC. The reaction was diluted with brine and extracted withDCM (3×). The combined layers were dried with MgSO₄, filtered andconcentrated. The crude residue was purified via chromatography, thefirst attempt was with EtOAc:Hexane:TEA (6:4:0.5) which failed togive >95% chemical purity. The purification was repeated with 10%MeOH/DCM to afford 0.081 g (21% yield) of TRV-1552 as a waxy solid. ¹HNMR (500 MHz, DMSO) δ=7.00 (s, 1H), 5.84 (s, 1H), 4.34 (t, J=10 Hz, 2H),3.92 (t, J=10 Hz, 2H), 3.56 (br s, 2H), 3.29-3.24 (m, 2H), 2.98-2.97 (m,1H), 2.72 (br s, 2H), 2.49 (overlapping with DMSO signal, br s, 4H),1.68 (s, 4H), 1.61-1.59 (m, 2H), 1.56 (s, 2H), 1.46 (s, 2H).

A round-bottomed flask was charged with TRV-1472 (600 mg, 1.78 mmol),benzyltriethylammonium (406 mg, 1.78 mmol) and Pd(OAc)₂ (40 mg, 0.178mmol). The flask was purged with nitrogen for several times, and thendry DMF (8 ml) allyl alcohol (0.181 ml, 2.67 mmol) and TEA (2.47 ml,17.8 mmol) were added to the mixture separately. The resulting mixturewas then heated to 55-60° C., and checked with TLC. After the reactionwas completed, 50 ml of EtOAc was added to the mixture. The mixture waswashed with brine for 3 times. The organic layer was dried andconcentrated.3-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)propanal(340 mg, 60.7%) was obtained via gradient elution (5:100:500,TEA/EtOAc/Hexane to 4:5:100:500 MeOH/TEA/EtOAc/Hexane). ¹H NMR (400 MHz,CDCl₃): 1.78-1.83 (m, 4H), 2.52 (s, br, 4H), 2.78-2.84 (m, 4H),2.91-2.94 (m, 2H), 3.01-3.07 (m, 1H), 3.95-3.97 (m, 2H), 4.38 (t, J=8.2,2H), 5.63 (s, 1H), 6.77 (s, 1H), 9.85 (s, 1H).

The above aldehyde (250 mg, 0.79 mmol) was cool to 0° C. in dry THFsolution (6 ml) under nitrogen atmosphere. TMSCF₃ (140 ul, 0.95 mmol)and TBAF (0.08 ml, 0.08 mmol, 1M solution) were added slowly to themixture separately. The colour was changed from red to purple and backto red during the addition. The solution was stirred for 2 hour at 0° C.After completion checked by TLC, the mixture was added with 5 ml ofwater and stirred for 1 h. This mixture was added with 50 ml of EtOAcand washed with 1 N NaOH and brine. The organic layer was dried overanhydrous sodium sulphate and then concentrated. The product (TRV-1553,220 mg, 72.6%) was obtained via gradient elution (5:100:500,TEA/EtOAc/Hexane to 4:5:100:500 MeOH/TEA/EtOAc/Hexane). ¹H NMR (400 MHz,CDCl₃): 1.85 (s, br, 4H), 1.92-2.08 (m, 2H), 2.54 (s, br, 4H), 2.70-2.78(m, 1H), 2.80 (d, J=7.6, 2H), 2.86-2.93 (m, 1H), 3.02-3.09 (m, 1H),3.92-3.97 (m, 3H), 4.40 (t, J=8.2, 2H), 5.67 (s, 1H), 6.82 (s, 1H).

n-BuLi (0.96 ml, 2.4 mmol, 4 M solution) was added dropwise to a stirredsolution of TRV-1472 (674 mg, 2 mmol) in THF (10 mL) at −78° C. undernitrogen atmosphere. After 20 minutes, a THF solution (5 ml) of1-Boc-2-piperidone (440 mg, 2.2 mmol) was added to the mixture at −78°C., and the black solution was stirred for 1 hour and the quench withMeOH. After addition of EtOAc (50 ml), the mixture was washed with 1 NNaOH and brine. The organic layer was dried and concentrated. tert-butyl(5-oxo-5-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pentyl)carbamate (360 mg, 39.3%) was obtained via gradient elution (5:100:500,TEA/EtOAc/Hexane to 2:5:100:500 MeOH/TEA/EtOAc/Hexane). ¹H NMR (400 MHz,CDCl₃): 1.45 (s, 9H), 1.56-1.60 (m, 2H), 1.74-1.82 (m, 6H), 2.53 (s, br,4H), 2.79 (d, J=7.6, 2H), 3.00-3.09 (m, 3H), 3.17-3.20 (m, 2H),4.00-4.04 (m, 2H), 4.45 (t, J=8.2, 2H), 4.63 (s, br, 1H), 6.34 (s, 1H),7.61 (s, 1H).

tert-Butyl(5-oxo-5-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pentyl)carbamate (280 mg, 1.0 mmol) was stirred in the solution of DCM/CF₃COOH(2:1, 3 ml) for 1 hour at 0° C. After completion checked by TLC, themixture was carefully neutralized with saturated K₂CO₃ solution until nomore gas gave out at 0° C. 15 ml of NaOH (2N) was added to the solution,and extracted with of DCM (3×10 ml). The organic layer was dried overanhydrous sodium sulphate and then concentrated. The residue(4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(3,4,5,6-tetrahydropyridin-2-yl)benzo[c][1,2,5]oxadiazole)was used for the next step without further purification. NaBH₄ (114 mg,1.83 mmol) was added to the solution of stirred in the solution of4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(3,4,5,6-tetrahydropyridin-2-yl)benzo[c][1,2,5]oxadiazole(210 mg, 0.61 mmol) in MeOH (8 ml) for 2 hour at rt. After completionchecked by TLC, the mixture was concentrated. 15 ml of NaOH (2N) wasadded to the residue, and extracted with of DCM (3×10 ml). The organiclayer was dried over anhydrous sodium sulphate and then concentrated.The residue (compound 3) was used for the next step without furtherpurification. TEA (0.51 ml, 3.66 mmol) and methanesulfonyl chloride(0.14 ml, 1.83 mmol) were added dropwise to a solution of6-(piperidin-2-yl)-4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(crude, 0.61 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 3 hours. After completion checked by TLC, the reaction wasquenched by EtOAc/H₂O (1:1, 50 ml). The mixture was washed with 2 N NaOHand brine. The organic layer was dried and concentrated. The residue waspurified via gradient elution (5:100:500, TEA/EtOAc/Hexane to4:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford Compound TRV-1554 (192 mg75%) as yellow solid. ¹H NMR (400 MHz, CDCl₃): 1.56-1.76 (m, 4H), 1.81(s, br, 4H), 1.95-2.02 (m, 1H), 2.34 (d, J=8.0, 1H), 2.54 (s, br, 4H),2.80 (d, J=7.6, 2H), 2.9 (s, 3H), 3.02-3.16 (m, 2H), 3.85 (d, J=7.2,1H), 3.97-4.00 (m, 2H), 4.39-4.43 (m, 2H), 5.01 (d, J=4.8, 1H), 5.88 (s,1H), 7.00 (s, 1H).

TEA (0.81 ml, 5.84 mmol) and acetic anhydride (0.276 ml, 2.92 mmol) wereadded to a solution of6-(piperidin-2-yl)-4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(200 mg, 0.584 mmol) in DCM (10 ml) at rt respectively. The mixture wasstirred for 2 hours. After completion checked by TLC, the reaction wasquenched by EtOAc/H₂O (1:1, 50 ml). The mixture was washed with 2 N NaOHand brine. The organic layer was dried and concentrated. The residue waspurified via gradient elution (5:100:500, TEA/EtOAc/Hexane to3:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford TRV-1555 (205 mg 91%) asyellow solid. ¹H NMR (400 MHz, CDCl₃): 1.52-1.89 (m, 9H), 2.13-2.34 (m,4H), 2.53 (s, br, 4H), 2.73-2.80 (m, 2.31H), 3.04-3.12 (m, 1.69H),3.69-3.72 (m, 0.69H), 3.95 (s, br, 2H), 4.34-4.41 (m, 2H), 4.63-4.65 (m,0.31H), 4.95 (s, br, 0.31H), 5.61-5.67 (m, 1H), 5.88 (s, 0.69H), 6.88(s, 1H).

Potassium carbonate (828 mg, 6 mmol) and 2-bromo-ethyl methyl ether(0.432 ml, 4.5 mmol) were added to a solution of6-(piperidin-2-yl)-4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(513 mg, 1.5 mmol) in acetonitrile (10 ml) respectively. Then themixture was heated to 50° C. for overnight, another batch of2-bromo-ethyl methyl ether (0.144 ml, 1.5 mmol) was added and heated for8 h at 50° C. The reaction was quenched by EtOAc/H₂O (1:1, 50 ml). Themixture was washed with 2 N NaOH and brine. The organic layer was driedand concentrated. The residue was purified via gradient elution(5:100:500, TEA/EtOAc/Hexane to 2:5:100:500 MeOH/TEA/EtOAc/Hexane) toafford TRV-1556 (280 mg, 46%) as red oil. ¹H NMR (400 MHz, CDCl₃):1.31-1.42 (m, 1H), 1.59-1.82 (m, 9H), 2.09-2.18 (m, 2H), 2.54 (s, br,4H), 2.71-2.78 (m, 1H), 2.80 (d, J=7.6, 2H), 3.03-3.07 (m, 2H), 3.23 (d,J=7.6, 1H), 3.28 (s, 3H), 3.34-3.39 (m, 1H), 3.46-3.52 (m, 1H),3.95-3.99 (m, 2H), 4.41 (q, J=8.0, J=6.0, 2H), 6.04 (s, 1H), 6.91 (s,1H).

n-BuLi (0.48 ml, 2.5 M, 1.2 mmol) was added dropwise to a solution of6-(piperidin-2-yl)-4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(342 mg, 1.0 mmol) in THF (10 ml) at −78° C. After the mixture wasstirred for 5 minutes, methyl iodide (0.125 ml, 2.0 mmol) was added to asolution, and the mixture was stirred for 1 h at −78° C. The reactionwas quenched by EtOAc/H₂O (1:1, 50 ml). The mixture was washed with 2 NNaOH and brine. The organic layer was dried and concentrated. Theresidue was purified via gradient elution (5:100:500, TEA/EtOAc/Hexaneto 4:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford TRV-1557 (156 mg, 44%)as red oil. ¹H NMR (400 MHz, CDCl₃): 1.31-1.41 (m, 1H), 1.55-1.72 (m,4H), 1.77-1.82 (m, 5H), 2.03-2.13 (m, 4H), 2.54 (s, br, 4H), 2.75-2.81(m, 3H), 3.00-3.08 (m, 2H), 3.94-4.00 (m, 2H), 4.39-4.44 (m, 2H), 5.99(s, 1H), 6.90 (s, 1H).

A reaction vial was charged with TRV 1472 (0.25 g, 0.74 mmol),(2,4,6-trimethylphenyl)boronic acid (0.16 g, 1.00 mmol), and Pd(PPh₃)₄(0.043 g, 0.037 mmol). The vial was degassed and refilled with nitrogen.To the vial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0M, 4.0 mmol). The reaction was re-degassed, refilled with nitrogen, andthen heated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 5:1:75:15) to afford 0.21 g (75% yield) of TRV1558 as red oil. ¹H NMR (CDCl₃, 400 MHz) δ=6.96 (d, J=0.50 Hz, 2H), 6.79(d, J=0.75 Hz, 1H), 5.62 (s, 1H), 4.40 (t, J=8.28 Hz, 2H), 3.97 (dd,J₁=5.90 Hz, J₂=8.16 Hz, 2H), 3.05 (septet, J=7.06 Hz, 1H), 2.82 (d,J=7.53 Hz, 2H), 2.58-2.49 (m, 4H), 2.35 (s, 3H), 2.10 (s, 6H), 1.85-1.76(m, 4H).

A reaction vial was charged with TRV 1472 (0.16 g, 0.47 mmol),(2,5-dimethylphenyl)boronic acid (0.085 g, 0.57 mmol), and Pd(PPh₃)₄(0.030 g, 0.026 mmol). The vial was degassed and refilled with nitrogen.To the vial was added dioxane (4 mL) and aq. sodium carbonate (2 mL, 2.0M, 4.0 mmol). The reaction was re-degassed, refilled with nitrogen, andthen heated to 90° C. until the reaction was complete. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography(TEA:MeOH:hexane:EtOAc 5:1:75:15) to afford 0.17 g (100% yield) of TRV1559 as red oil. ¹H NMR (CDCl₃, 400 MHz) δ=7.18 (d, J=7.78 Hz, 1H), 7.12(d, J=7.78 Hz, 1H), 7.09 (s, 1H), 6.90 (d, J=0.75 Hz, 1H), 5.79 (s, 1H),4.42 (t, J=8.28 Hz, 2H), 3.99 (dd, J₁=5.77 Hz, J₂=8.53 Hz, 2H), 3.06(septet, J=7.15 Hz, 1H), 2.81 (d, J=7.28 Hz, 2H), 2.60-2.48 (m, 4H),2.37 (s, 3H), 2.27 (s, 3H), 1.87-1.75 (m, 4H).

A reaction vial was charged with4-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tri-n-butylstannyl)benzo[c][1,2,5]oxadiazole(0.33 g, 0.60 mmol), 2-bromothiazole (0.081 mL, 0.90 mmol), Pd(PPh₃)₄(0.035 g, 0.030 mmol), Cul (0.011 g, 0.06 mmol), and CsF (0.18 g, 1.20mmol). The vial was degassed and refilled with nitrogen. To the vial wasadded NMP (4 mL). The reaction was re-degassed, refilled with nitrogen,sealed, and then heated to 50° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate and concentrated. The residue was purified by flashchromatography using gradient elution (TEA:MeOH:hexane:EtOAc 5:0:75:15to TEA:MeOH:hexane:EtOAc 5:3:75:15) to afford 0.086 g (42% yield) of TRV1560 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.93 (d, J=3.26 Hz, 1H),7.56 (s, 1H), 7.44 (d, J=3.26 Hz, 1H), 6.56 (s, 1H), 4.50 (t, J=8.53 Hz,2H), 4.07 (dd, J₁=6.02 Hz, J₂=8.53 Hz, 2H), 3.09 (septet, J=7.53 Hz,1H), 2.81 (d, J=7.28 Hz, 2H), 2.58-2.50 (m, 4H), 1.85-1.77 (m, 4H).

A reaction vial was charged with4-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tri-n-butylstannyl)benzo[c][1,2,5]oxadiazole(0.41 g, 0.75 mmol), 4-bromothiazole (0.10 mL, 1.13 mmol), Pd(PPh₃)₄(0.043 g, 0.037 mmol), Cul (0.014 g, 0.076 mmol), and CsF (0.28 g, 1.86mmol). The vial was degassed and refilled with nitrogen. To the vial wasadded DMF (4 mL). The reaction was re-degassed, refilled with nitrogen,sealed, and then heated to 50° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate and concentrated. The residue was purified by flashchromatography using gradient elution (TEA:MeOH:hexane:EtOAc 5:0:75:15to TEA:MeOH:hexane:EtOAc 5:3:75:15) to afford 0.11 g (43% yield) of TRV1561 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.91 (d, J=2.01 Hz, 1H),7.68 (d, J=2.01 Hz, 1H), 7.59 (s, 1H), 6.44 (s, 1H), 4.48 (t, J=8.28 Hz,2H), 4.05 (dd, J₁=5.77 Hz, J₂=8.53 Hz, 2H), 3.09 (septet, J=7.00 Hz,1H), 2.81 (d, J=7.28 Hz, 2H), 2.59-2.49 (m, 4H), 1.85-1.75 (m, 4H).

6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole (0.427 g, 2.0 mmol) and5-formylthiophene-2-boronic acid (0.340 g, 2.2 mmol) were added to aglass tube and the tube was evacuated and purged with argon (3×). DME(2.8 mL) and Na₂CO₃ (3.0 mL, 6 mmol, 2 N aqueous solution) were addedfollowed by Pd (PPh₃)₄ (0.115 g, 0.1 mmol). The tube was sealed and thenheated to 80° C. overnight. The reaction was cooled and then dilutedwith EtOAc and water. The organic layer was washed with water (3×),brine, dried (MgSO₄), filtered and concentrated to give5-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiophene-2-carbaldehyde whichwas purified using column chromatography and used in next step.

5-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiophene-2-carbaldehyde (0.2g) was dissolved in THF (5 mL) and cooled in an ice bath. CF₃TMS (0.19mL) was added and then the catalyst TBAF (0.1 mL, 1.0 M solution) wasadded. After 30 minutes the reaction was removed from the ice bath andallowed to warm to room temperature.

Once complete by TLC, recooled to 0° C. and 2 N HCl (aq) was added,stirred for 40 minutes and then basified with 2N NaOH. This mixture wasextracted with EtOAc. The combined extracts were washed with water (2×),brine, filtered and concentrated. The crude material was purified viachromatography (hexane:ethyl acetate, 80:20) to afford 0.2 mg (80%) of2, 2,2-trifluoro-1-(5-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiophen-2-yl)ethan-1-olas yellow solid. ¹H NMR (400 MHz, CDCl3) δ 7.82 (s 1H), 7.42 (d, J=4.0Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 5.33-5.38 (m,1H), 2.88 (d, J=8.0 Hz, 1H).

2, 2,2-trifluoro-1-(5-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiophen-2-yl)ethan-1-ol(0.172 g, 0.54 mmol) and 4-(azetidin-3-ylmethyl)morpholine hydrochloridesalt (0.185 g, 0.81 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.3 ml, 2.16 mmol) was added and mixture washeated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give2,2,2-trifluoro-1-(5-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)thiophen-2-yl)ethan-1-olTRV1562. ¹H NMR (DMSO, 700 MHz) δ=7.77 (d, J=5 Hz, 1H), 7.56 (s, 1H),7.42 (d, J=5 Hz, 1H), 7.28 (d, J=5 Hz, 1H), 6.76 (s, 1H), 5.59-5.55 (m,1H), 4.38 (m, 2H), 3.96 (m, 2H), 3.54 (m, 4H), 3.08 (m, 1H), 2.64 (d,J=8.0 Hz, 2H), 2.39 (m, 4H)

2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl)morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give2,2,2-trifluoro-1-(2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-ol TRV-1563.Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain the title Compound(0.105 g, 80%) as orange color solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.70(d, J=4.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.60 (m, 1H), 7.12 (s, 1H),7.05 (s, 1H), 5.93 (s, 1H), 5.28 (m, 1H), 4.37 (m, 2H), 3.94 (m, 2H),3.56 (m, 4H), 3.05 (m, 1H), 2.63 (d, J=8.0 Hz, 2H), 2.37 (m, 4H).

2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-ol(0.1, 0.32 mmol) and 1-(azetidin-3-ylmethyl)pyrrolidine hydrochloridesalt (0.102 g, 0.48 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give 2, 2,2-trifluoro-1-(2-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) pyridin-3-yl) ethan-1-ol TRV1564.Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain the title Compound(0.103 g, 78%) as orange color solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.70(d, J=4.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.60 (m, 1H), 7.12 (s, 1H),7.04 (s, 1H), 5.93 (s, 1H), 5.27 (m, 1H), 4.37 (m, 2H), 3.94 (m, 2H),3.02 (m, 1H), 2.72 (d, J=8.0 Hz, 2H), 2.43 (m, 4H), 1.67 (m, 4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.33 g, 1.25 mmol), 2-bromothiazole-4-carbaldehyde (0.19 g, 1.00 mmol),Pd(PPh₃)₄ (0.058 g, 0.050 mmol). The vial was degassed and refilled withnitrogen. To the vial was added dioxane (4 mL) and aq. Na₂CO₃ (2 mL, 2.0M, 5.0 mmol). The reaction vial was re-degassed, refilled with nitrogen,sealed, and then heated to 90° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate and concentrated. The residue was purified by flashchromatography using gradient elution (EtOAc:Hex 0:100 to 10:90) toafford 0.13 g (51% yield) of2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-4-carbaldehyde as acolorless solid. To a solution of2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-4-carbaldehyde (0.13g, 0.51 mmol) in THF (5 mL) was added sodium borohydride (0.15 g, 4.07mmol). The reaction mixture was stirred at rt until it was complete. Thereaction was cooled in an ice-water bath, quenched with saturatedammonium chloride, and extracted with ethyl acetate. The ethyl acetatephase was dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash chromatography using gradient elution(EtOAc:Hex 0:100 to 20:80) to afford 0.070 g (53% yield) of(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-4-yl)methanol as acolorless solid.

To a solution of(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-4-yl)methanol (0.070g, 0.27 mmol) in acetonitrile (5 mL) was added1-(azetidin-3-ylmethyl)morpholine dihydrochloride (0.093 g, 0.41 mmol)followed by TEA (0.14 mL, 1.03 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:0:25:75 to 5:10:25:75) to afford 0.086 g (80%yield) of TRV 1565 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.55 (s,1H), 7.30 (s, 1H), 6.31 (s, 1H), 4.87 (s, 2H), 4.48 (t, J=8.28 Hz, 2H),4.07 (dd, J₁=5.52 Hz, J₂=8.53 Hz, 2H), 3.74 (t, J=4.65 Hz, 4H), 3.10(septet, J=6.65 Hz, 1H), 2.72 (d, J=7.28 Hz, 2H), 2.49 (t, J=4.39 Hz,4H), 2.40 (broad, 1H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.33 g, 1.25 mmol), 4-bromothiazole-2-carbaldehyde (0.19 g, 1.00 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(H) (0.016 g, 0.020 mmol). The vialwas degassed and refilled with nitrogen. To the vial was added dioxane(3 mL) and aq. K₃PO₄ (3 mL, 0.68 M, 2.0 mmol). The reaction vial wasre-degassed, refilled with nitrogen, sealed, and then heated to 80° C.overnight. The mixture was diluted with water, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography usinggradient elution (EtOAc:Hex 0:100 to 10:90) to afford 0.15 g (59% yield)of 4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-2-carbaldehyde as acolorless solid.

To a solution of4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-2-carbaldehyde (0.15g, 0.59 mmol) in THF (5 mL) was added sodium borohydride (0.067 g, 1.77mmol). The reaction mixture was stirred at rt until it was complete. Thereaction was cooled in an ice-water bath, quenched with saturatedammonium chloride, and extracted with ethyl acetate. The ethyl acetatephase was dried over anhydrous sodium sulfate and concentrated. Theresidue was dissolved in acetonitrile (5 mL). To the solution was added1-(azetidin-3-ylmethyl) morpholine dihydrochloride (0.17 g, 0.74 mmol)followed by TEA (0.26 mL, 1.87 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:1:25:75 to 5:10:25:75) to afford 0.15 g (66% yieldfor two steps) TRV1566 as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.60(s, 1H), 7.55 (s, 1H), 6.37 (s, 1H), 5.04 (s, 2H), 4.45 (t, J=8.16 Hz,2H), 4.07 (dd, J₁=5.52 Hz, J₂=8.28 Hz, 2H), 3.74 (t, J=4.65 Hz, 4H),3.09 (septet, J=6.86 Hz, 1H), 2.78 (broad, 1H), 2.72 (d, J=7.53 Hz, 2H),2.39 (t, J=4.39 Hz, 4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.29 g, 1.08 mmol), 1-(4-bromothiazol-2-yl)-2,2,2-trifluoroethan-1-ol(0.22 g, 0.83 mmol), Pd(PPh₃)₄ (0.048 g, 0.042 mmol). The vial wasdegassed and refilled with nitrogen. To the vial was added dioxane (4mL) and aq. Na₂CO₃ (2 mL, 2.0 M, 5.0 mmol). The reaction vial wasre-degassed, refilled with nitrogen, sealed, and then heated to 90° C.until the reaction was complete. The mixture was diluted with water,added 3 mL of 2N NaOH, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:Hex 0:100 to 15:85) to afford 0.050 g (19% yield) of2,2,2-trifluoro-1-(4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-2-yl)ethan-1-olas a colorless solid.

To a solution of2,2,2-trifluoro-1-(4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-2-yl)ethan-1-ol(0.050 g, 0.16 mmol) in acetonitrile (5 mL) was added1-(azetidin-3-ylmethyl)pyrrolidine dihydrochloride (0.050 g, 0.24 mmol)followed by TEA (0.09 mL, 0.62 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:1:25:75 to 5:5:25:75) to afford 0.050 g (72%yield) TRV 1567 as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.73 (s,1H), 7.58 (s, 1H), 6.29 (s, 1H), 5.38 (q, J=7.27 Hz, 1H), 4.47 (t,J=8.28 Hz, 2H), 4.07-4.00 (m, 2H), 3.09 (septet, J=7.03 Hz, 1H), 2.83(d, J=7.28 Hz, 2H), 2.61-2.52 (m, 4H), 1.87-1.78 (m, 4H).

2, 2,2-trifluoro-1-(4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiophen-2-yl)ethan-1-ol(0.1, 0.31 mmol) and 4-(azetidin-3-ylmethyl)morpholine hydrochloridesalt (0.108 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.25 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give 2, 2,2-trifluoro-1-(4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) thiophen-2-yl) ethan-1-ol TRV 1568.Purification was done on ISCO flash Chromatography system usingdichloromethane:methanol (95:5) solvent system to obtain the titleCompound (0.118 g, 83%) as orange color solid. ¹H NMR (DMSO-d6, 400MHz): δ 8.23 (s, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.35 (d, J=8.0 Hz,1H), 6.36 (s, 1H), 5.50 (m, 1H), 4.37 (m, 2H), 3.95 (m, 2H), 3.57 (m,4H), 3.06 (m, 1H), 2.64 (d, J=8.0 Hz, 2H), 2.39 (m, 2H).

2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl)morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give 2, 2,2-trifluoro-1-(3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) pyridin-2-yl) ethan-1-ol TRV1569.Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain the title Compound(0.105 g, 80%) as orange color solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.72(d, J=4.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.48 (m, 1H), 6.93 (s, 1H),5.67 (s, 1H), 5.33 (m, 1H), 4.98 (d, J=8.0 Hz, 1H), 4.43 (m, 2H), 4.02(m, 2H), 3.72 (m, 4H), 3.10 (m, 1H), 2.73 (d, J=4.0 Hz, 2H), 2.48 (m,4H).

CuCN (594 mg, 6.6 mmol) and TRV1470 (1.06 g, 3.0 mmol) were added to dryNMP (8 ml). The vial was purged with nitrogen for several times. Themixture was heated to 150° C. and stirred for 10 hours. After completionchecked by TLC, the reaction was quenched with aqueous ammonia hydroxide(5 ml), and EtOAc (50 ml) was added to the solution. The mixture waswashed with 1 N NaOH and brine. The organic layer was dried andconcentrated. The residue was purified via gradient elution (5:100:500,TEA/EtOAc/Hexane to 2:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carbonitrile TRV1570 (708 mg, 79%) as a redsolid. ¹H NMR (400 MHz, CDCl₃): 2.44-2.49 (m, 4H), 2.72 (d, J=7.6, 2H),3.08-3.15 (m, 1H), 3.69-3.76 (m, 4H), 4.05-4.11 (m, 2H), 4.45-4.49 (m,2H), 5.83 (s, 1H), 7.40 (s, 1H).

n-BuLi (2.22 ml, 2.5 M, 5.56 mmol) was added dropwise to a solution ofTRV1470 (1.51 mg, 4.28 mmol) in THF (20 ml) at −78° C. under nitrogenatmosphere. After the mixture was stirred for 10 minutes, DMF (0.46 ml,6.0 mmol) was added to a solution, and the mixture was stirred for 1 hat −78° C. The reaction was quenched by MeOH (1 ml), and EtOAc (50 ml)was added to the solution. The mixture was washed with 1 N NaOH andbrine. The organic layer was dried and concentrated. The residue waspurified via gradient elution (5:100:500, TEA/EtOAc/Hexane to2:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carbaldehyde(980 mg, 76%) as red solid.

NaBH₄ (370 mg, 9.73 mmol) was added to a solution of7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carbaldehyde (980 mg, 3.24 mmol) in MeOH (10ml) at room temperature. After the mixture was stirred for 1 hour, thereaction was quenched by EtOAc/H₂O (1:1, 50 ml). The mixture was washedwith 1 N NaOH and brine. The organic layer was dried and concentrated.The residue was purified via gradient elution (5:100:500,TEA/EtOAc/Hexane to 10:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)methanolTRV1571 (560 mg, 56%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): 1.94(s, br, 1H), 2.46-2.48 (m, 4H), 2.70 (d, J=7.6, 2H), 3.03-3.10 (m, 1H),3.72-3.74 (m, 4H), 3.95-3.98 (m, 2H), 4.39 (t, J=8.2, 2H), 4.68 (s, 2H),5.81 (s, 1H), 7.01 (s, 1H).

A reaction vial was charged with6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(1.20 g, 3.40 mmol), (2-formylphenyl)boronic acid (0.76 g, 5.07 mmol),Pd(PPh₃)₄ (0.20 g, 0.17 mmol). After degassed and refilled withnitrogen, the vial was charged with dioxane (15 mL) and aq. Na₂CO₃ (6mL, 2.0 M, 12.0 mmol). The reaction vial was further re-degassed,refilled with nitrogen, sealed, and then heated to 100° C. until thereaction was complete. The mixture was diluted with water, added 5 mL of2N NaOH, and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:0:15:75 to 5:2:15:75) to afford 0.93 g (73% yield)of2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzaldehydeas a yellow semi-solid.

A solution of2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzaldehyde(0.20 g, 0.53 mmol) in THF (5 mL) was cooled in an ice-water bath. Tothe cooled solution was added sodium borohydride (0.060 g, 1.60 mmol) inportion. The reaction mixture was stirred until it was complete, thenquenched with 1N aq. HCl, basified with 1N NaOH, and then extracted withethyl acetate. The ethyl acetate phase was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flashchromatography using gradient elution (TEA:MeOH:EtOAc:Hex 5:0:25:75 to5:5:25:75) to afford 0.12 g (60% yield) of the TRV1572 as red oil. ¹HNMR (CDCl₃, 400 MHz) δ=7.59 (d, J=7.53 Hz, 1H), 7.45 (dt, J₁=1.25 Hz,J₂=7.53 Hz, 1H), 7.39 (dt, J₁=1.25 Hz, J₂=7.53 Hz, 1H), 7.33 (dd,J₁=1.51 Hz, J₂=7.53 Hz, 1H), 6.97 (s, 1H), 5.86 (s, 1H), 4.68 (d, J=4.27Hz, 2H), 4.41 (t, J=8.28 Hz, 2H), 3.99 (dd, J₁=5.77 Hz, J₂=8.53 Hz, 2H),3.72 (t, J=4.65 Hz, 4H), 3.07 (septet, J=6.59 Hz, 1H), 2.72 (d, J=7.53Hz, 2H), 2.47 (t, J=4.39 Hz, 4H), 1.67 (broad, 1H).

TRV1470 (0.250 g, 0.7 mmol) and 3, 4-dimethoxybenzeneboronic acid (0.155g, 0.85 mmol) were sealed in a tube. The tube was evacuated and purgedwith argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) was addedalong with Dioxane (5 mL). The solution was degassed for 10 minutes andthen Pd(PPh₃)₄ (0.041 g, 0.035 mmol) was added all at once. The tube wasre-sealed and heated to 80° C. overnight. After cooling to roomtemperature, the mixture was diluted with water and EtOAc. The layerswere separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography on ISCO (3% MeOH/DCM) to afford 0.238 g (82%yield) of 6-(3, 4-dimethoxyphenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1573. ¹H NMR (CDCl3, 500 MHz) δ=7.22 (dd,J=4.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.12 (s, 1H), 6.98 (d, J=8.0 Hz,1H), 6.06 (s, 1H), 4.47 (t, J=8.0 Hz, 2H), 4.07 (m, 2H), 3.98 (s, 3H),3.96 (s, 3H), 3.74 (m, 4H), 3.10-3.06 (m, 1H), 2.74 (d, J=8.0 Hz, 2H),2.49 (m, 4H).

A round-bottomed flask was charged with TRV1470 (250 mg, 0.7 mmol),(4-cyanophenyl) boronic acid (125 mg, 0.85 mmol), and Pd (PPh₃)₄ (42 mg,0.035 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate(1.5 mL, 2M) was added. The reaction mixture was heated to 80° C. for 3h. After completion checked by TLC, 10 mL of water was added, and thereaction mixture was extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate and then concentrated. The residuewas purified on ISCO column chromatography system (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 219 mg (83% yield) of4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzonitrile TRV1574 as a red solid. ¹HNMR (400 MHz, CDCl₃): δ 7.78 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H),7.16 (s, 1H), 5.97 (s, 1H), 4.49 (t, J=8.0 Hz, 2H), 4.07 (t, J=8.0 Hz,2H), 3.74 (m, 4H), 3.15 (m, 1H), 2.74 (d, J=8.0 Hz, 2H), 2.48 (m, 4H).

TRV-1470 (0.250 g, 0.7 mmol) and (3, 5-dichlorophenyl) boronic acid(0.162 g, 0.85 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) wasadded along with Dioxane (5 mL). The solution was degassed for 10minutes and then Pd (PPh₃)₄ (0.041 g, 0.035 mmol) was added all at once.The tube was re-sealed and heated to 80° C. for 3 h. After cooling toroom temperature, the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography on ISCO (2% MeOH/DCM) to afford 0.255 g (86%yield) of 6-(3, 5-dichlorophenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1575. ¹H NMR (CDCl3, 400 MHz) δ=7.48 (m,2H), 7.42 (m, 1H), 7.11 (s, 1H), 5.99 (s, 1H), 4.49 (t, J=8.0 Hz, 2H),4.06-4.03 (m, 2H), 3.74 (m, 4H), 3.14-3.08 (m, 1H), 2.74 (d, J=8.0 Hz,2H), 2.49 (m, 4H).

3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)benzamide (0.102 g, 0.4 mmol)and 4-(azetidin-3-ylmethyl)morpholine hydrochloride salt (0.137 g, 0.6mmol) were dissolved in NMP (5 ml) at room temperature, triethylamine(0.22 ml, 1.6 mmol) was added and mixture was heated at 80° C. for 2 h.After completion of reaction by TLC it was quenched with Na2CO3 (2M) andextracted with EtOAC to give 3-(7-(3-(morpholinomethyl) zetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) benzamide TRV1576. Purification was doneon ISCO flash Chromatography system using dichloromethane:methanol(95:5) solvent system to obtain the title Compound (0.128 g, 80%) asorange color solid. ¹H NMR (DMSO-d6, 400 MHz): δ 8.22 (s, 1H), 8.16 (s,1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.51 (s, 1H),7.41 (s, 1H), 6.31 (s, 1H), 4.40 (t, J=8.0 Hz, 2H), 3.98 (m, 2H), 3.58(m, 4H), 3.09-3.02 (m, 1H), 2.63 (d, J=4.0 Hz, 2H), 2.38 (m, 2H).

A round-bottomed flask was charged with TRV-1470 (250 mg, 0.7 mmol),(3-cyanophenyl) boronic acid (125 mg, 0.85 mmol), and Pd(PPh₃)₄ (42 mg,0.035 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate(1.5 mL, 2M) was added. The reaction mixture was heated to 80° C. for 3h. After completion checked by TLC, 10 mL of water was added, and thereaction mixture was extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate and then concentrated. The residuewas purified on ISCO column chromatography system (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 250 mg (94% yield) of3-(7-(3-(morpholinomethyl) azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzonitrile TRV1577 as a red solid. ¹HNMR (400 MHz, CDCl₃): δ 7.90 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.73 (d,J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 5.95 (s, 1H), 4.49(t, J=8.0 Hz, 2H), 4.07 (t, J=8.0 Hz, 2H), 3.74 (m, 4H), 3.12 (m, 1H),2.74 (d, J=4.0 Hz, 2H), 2.50 (m, 4H),

TRV1470 (0.250 g, 0.7 mmol) and (3-chloro-4-methoxyphenyl) boronic acid(0.158 g, 0.85 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) wasadded along with Dioxane (5 mL). The solution was degassed for 10minutes and then Pd (PPh₃)₄ (0.041 g, 0.035 mmol) was added all at once.The tube was re-sealed and heated to 80° C. for 3 h. After cooling toroom temperature, the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography on ISCO (2% MeOH/DCM) to afford 0.225 g (78%yield) of6-(3-chloro-4-methoxyphenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1578. ¹H NMR (CDCl₃, 400 MHz) δ=7.65 (d,J=4.0 Hz, 1H), 7.52-7.49 (dd, J=4.0 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=8Hz, 1H), 5.99 (s, 1H), 4.47 (t, J=8.0 Hz, 2H), 4.04-4.01 (m, 2H), 3.97(s, 3H), 3.74 (m, 4H), 3.13-3.06 (m, 1H), 2.74 (d, J=8.0 Hz, 2H), 2.49(m, 4H).

4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)benzamide (0.102 g, 0.4 mmol)and 1-(azetidin-3-yl methyl) pyrrolidinehydrochloride salt (0.128 g, 0.6mmol) were dissolved in NMP (5 ml) at room temperature, triethylamine(0.22 ml, 1.6 mmol) was added and mixture was heated at 80° C. for 2 h.After completion of reaction by TLC it was quenched with Na2CO3 (2M) andextracted with EtOAC to give4-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzamide TRV1579. Purification was doneon ISCO flash Chromatography system using dichloromethane:methanol(95:5) solvent system to obtain the title Compound (0.110 g, 73%) asorange color solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.08 (bs, 1H), 7.99 (d,J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.46 (bs, 1H), 7.40 (s, 1H), 6.30(s, 1H), 4.41 (t, J=8.0 Hz, 2H), 4.0 (t, J=8.0 Hz, 2H), 3.04-2.99 (m,1H), 2.80 (m, 2H), 2.40 (m, 2H), 1.69 (m, 4H).

A reaction vial was charged with4-(3-(Pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tri-n-butylstannyl)benzo[c][1,2,5]oxadiazole(0.25 g, 0.74 mmol), 2-bromopyridine (0.90 mmol), Pd(PPh₃)₄ (35 mg,0.030 mmol), Cul (11.4 mg, 0.06 mmol), and Cs₂CO₃ (182 mg, 1.20 mmol).The vial was degassed and refilled with nitrogen. To the vial was addedNMP (4 mL). The reaction was re-degassed, refilled with nitrogen,sealed, and then heated to 50° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The ethyl acetate phase was dried over anhydroussodium sulfate and concentrated. The residue was purified by flashchromatography (Combi-Flash RF200 system) to get6-(Pyridin-2-yl)-4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazoleTRV1580. ¹H NMR (CDCl₃, 400 MHz) δ=8.73 (d, J=4.52 Hz, 1H), 7.83-7.78(m, 2H), 7.52 (s, 1H), 7.35-7.30 (m, 1H), 6.65 (s, 1H), 4.50 (t, J=8.28Hz, 2H), 4.07 (dd, J₁=5.90 Hz, J₂=8.41 Hz, 2H), 3.09 (septet, J=6.90 Hz,1H), 2.81 (d, J=7.28 Hz, 2H), 2.58-2.50 (m, 4H), 1.85-1.77 (m, 4H).

TRV1470 (0.250 g, 0.7 mmol) and (4-fluoro-3-methoxyphenyl) boronic acid(0.145 g, 0.85 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) wasadded along with Dioxane (5 mL). The solution was degassed for 10minutes and then Pd (PPh₃)₄ (0.041 g, 0.035 mmol) was added all at once.The tube was re-sealed and heated to 80° C. for 3 h. After cooling toroom temperature, the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography on ISCO (2% MeOH/DCM) to afford 0.248 g (88%yield) of6-(4-fluoro-3-methoxyphenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1584. ¹H NMR (CDCl3, 400 MHz) δ=7.20-7.15(m, 3H), 7.10 (s, 1H), 5.99 (s, 1H), 4.47 (t, J=8.0 Hz, 2H), 4.04-4.01(m, 2H), 3.98 (s, 3H), 3.74 (m, 4H), 3.13-3.07 (m, 1H), 2.74 (d, J=8.0Hz, 2H), 2.48 (m, 4H).

TRV1470 (0.250 g, 0.7 mmol) and (3-fluoro-4-methoxyphenyl) boronic acid(0.145 g, 0.85 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) wasadded along with Dioxane (5 mL). The solution was degassed for 10minutes and then Pd (PPh₃)₄ (0.041 g, 0.035 mmol) was added all at once.The tube was re-sealed and heated to 80° C. for 3 h. After cooling toroom temperature, the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography on ISCO (2% MeOH/DCM) to afford 0.260 g (92%yield) of6-(3-fluoro-4-methoxyphenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1585. ¹H NMR (CDCl3, 400 MHz) δ=7.38-7.36(m, 2H), 7.10 (s, 1H), 7.07-7.03 (t, J=8 Hz, 1H), 5.99 (s, 1H), 4.46 (t,J=8.0 Hz, 2H), 4.04-4.02 (m, 2H), 3.96 (s, 3H), 3.75 (m, 4H), 3.13-3.06(m, 1H), 2.73 (d, J=8.0 Hz, 2H), 2.49 (m, 4H).

A round-bottomed flask was charged with TRV1470 (250 mg, 0.7 mmol),(2-cyanophenyl) boronic acid (125 mg, 0.85 mmol), and Pd (PPh₃)₄ (42 mg,0.035 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate(1.5 mL, 2M) was added. The reaction mixture was heated to 80° C. for 6h. After completion checked by TLC, 10 mL of water was added, and thereaction mixture was extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate and then concentrated. The residuewas purified on ISCO column chromatography system (2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford 150 mg (57% yield) of2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzonitrile TRV1586 as a red solid. ¹HNMR (400 MHz, CDCl₃): δ 7.84 (t, J=8.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H),7.49-7.59 (m, 2H), 7.10 (s, 1H), 5.96 (s, 1H), 4.49 (t, J=8.0 Hz, 2H),4.07 (t, J=8.0 Hz, 2H), 3.74 (m, 4H), 3.12 (m, 1H), 2.74 (d, J=8.0 Hz,2H), 2.48 (m, 4H).

4-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)-6-(tributylstannyl)benzo[c][1,2,5]oxadiazole(0.4 g, 0.73 mmol), 1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethan-1-ol(0.230 g, 0.9 mmol), CsF (0.45 g, 2.19 mmol), Cul (14 mg, 0.073 mmol),Pd(PPh3)4, (0.042 g, 0.0365 mmol) was charged in glass tube and sealed,it was then degassed and flushed with N2. DMF (10 ml) was added andreaction mixture was heated at 45° C. overnight. After completion ofreaction by TLC, the reaction was cooled and then diluted with EtOAc andwater. The organic layer was washed with water (3×), brine, dried(MgSO₄), filtered and concentrated to give the crude product which waspurified using column chromatography to give2,2,2-trifluoro-1-(2-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) pyridin-4-yl)ethan-1-ol TRV1587 (0.08 g,26%). ¹H NMR (400 MHz, CDCl3): δ 8.74 (d, J=4.0 Hz, 1H), 7.86 (s, 1H),7.47 (s, 1H), 7.43 (d, J=4.0 Hz, 1H), 6.39 (s, 1H), 5.09 (m, 1H), 4.42(m, 2H), 3.99 (m, 2H), 3.05 (m, 1H), 2.83 (d, J=8.0 Hz, 2H), 2.57 (m,4H), 1.84 (m, 4H).

TRV1470 (0.250 g, 0.7 mmol) and (3, 5-difluorophenyl) boronic acid(0.135 g, 0.85 mmol) were sealed in a tube. The tube was evacuated andpurged with argon (3 cycles). 2M Na₂CO₃ (1.2 mL, 2.0 M aq solution) wasadded along with Dioxane (5 mL). The solution was degassed for 10minutes and then Pd (PPh₃)₄ (0.041 g, 0.035 mmol) was added all at once.The tube was re-sealed and heated to 80° C. for 3 h. After cooling toroom temperature, the mixture was diluted with water and EtOAc. Thelayers were separated and the aqueous layer was then back-extracted. Thecombine organic extracts were then washed with H₂O (3×), brine and thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified via chromatography on ISCO (2% MeOH/DCM) to afford 0.240 g (88%yield) of 6-(3, 5-difluorophenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1588. ¹H NMR (CDCl₃, 400 MHz) δ=7.15-7.13(m, 3H), 6.89 (t, J=8.0 Hz, 1H), 5.94 (s, 1H), 4.48 (t, J=8.0 Hz, 2H),4.06-4.02 (m, 2H), 3.74 (m, 4H), 3.14-3.08 (m, 1H), 2.74 (d, J=8.0 Hz,2H), 2.49 (m, 4H).

TRV-1470 (0.5571 g, 1.58 mmol) and 4-formylphenylboronic acid (0.2606 g,1.74 mmol) were weighed into a tube. The tube was evacuated and purgedwith argon (3×). DME (3.5 mL) and aqueous Na₂CO₃ (2.4 mL, 2N aqsolution) was added to the tube. The tube was degassed for 5 minutes bybubbling argon gas through the solution. Pd(PPh₃)₄ (0.0924 g, 0.08 mmol)was added all at once, the tube was sealed and heated to 95° C. for 4hours. The reaction was then cooled to room temperature and diluted withDCM and water. The layers were separated and the aqueous layer wasback-extracted with DCM (2×). The combined organic layers were washedwith water, dried (MgSO₄), filtered and concentrated to give a crudebrown solid. This crude material was purified via flash chromatography(60% EtOAc/hexane with 5% TEA additive) to afford 0.5709 g (95% yield)of aldehyde 3 as an orange solid. Aldehyde 3 (0.2852 g, 0.75 mmol) wasdissolved in a mixture of MeOH (12.5 mL) and THF (5 mL) and then cooledin an ice bath. NaBH₄ (0.0567 g, 1.5 mmol) was then added all at once,and the mixture was stirred overnight while warming to room temperature.The reaction was then recooled to 0° C. and quenched with saturatedammonium chloride. The aqueous mixture was then made basic with 2N NaOH(aq) before extracting with DCM. The combined organic extracts weredried (MgSO₄), filtered and concentrated to give the crude benzylalcohol. This material was purified via flash chromatography (5%MeOH/DCM) to afford 0.1551 g (54% yield) of TRV1592 as an orange solid.¹H NMR (500 MHz, DMSO) δ=7.74 (d, J=8 Hz, 2H), 7.42 (d, J=8 Hz, 2H),7.30 (s, 1H), 6.27 (s, 1H), 5.24 (t, J=5.5 Hz, 1H), 4.55 (d, J=5.5 Hz,2H), 4.37 (t, J=8.5 Hz, 2H), 3.97-3.94 (m, 2H), 3.57 (t, J=4.5 Hz, 4H),3.09-3.01 (m, 1H), 2.63 (d, J=7.5 Hz, 2H), 2.38 (br s, 4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.40 g, 1.50 mmol), (2-bromothiazol-5-yl)methanol (0.23 g, 1.19 mmol),Pd(PPh₃)₄ (0.068 g, 0.059 mmol). After degassed and refilled withnitrogen, the vial was charged with dioxane (4 mL) and aq. Na₂CO₃ (2 mL,2.0 M, 5.0 mmol). The reaction vial was further re-degassed, refilledwith nitrogen, sealed, and then heated to 100° C. until the reaction wascomplete. The mixture was diluted with water, added 3 mL of 2N NaOH, andextracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (EtOAc:Hex 0:100 to 15:85)to afford 0.20 g (68% yield) of(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-5-yl)methanol as acolorless solid.

To a solution of(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-5-yl)methanol (0.20 g,0.80 mmol) in acetonitrile (5 mL) was added1-(azetidin-3-ylmethyl)pyrrolidine dihydrochloride (0.28 g, 1.20 mmol)followed by TEA (0.42 mL, 3.00 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:0:25:75 to 5:10:25:75) to afford 0.050 g (72%yield) of TRV1594 as an orange solid. ¹H NMR (DMSO, 400 MHz) δ=7.82 (s,1H), 7.59 (s, 1H), 6.51 (s, 1H), 5.72 (t, J=5.65 Hz, 1H), 4.74 (d,J=5.52 Hz, 2H), 4.39 (t, J=8.28 Hz, 2H), 4.00-3.91 (m, 2H), 3.57 (t,J=74.52 Hz, 4H), 3.06 (septet, J=6.71 Hz, 1H), 2.63 (d, J=7.53 Hz, 2H),2.42-2.34 (m, 4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.16 g, 0.61 mmol), 1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethan-1-ol(0.16 g, 0.61 mmol), Pd(PPh₃)₄ (35 mg, 0.030 mmol). The vial wasdegassed and refilled with nitrogen. To the vial was added dioxane (4mL) and aq. Na₂CO₃ (2 mL, 2.0 M, 4.0 mmol). The reaction vial wasre-degassed, refilled with nitrogen, sealed, and then heated to 90° C.until the reaction was complete. The mixture was diluted with water,added 3 mL of 2N NaOH, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:Hex 0:100 to 15:85) to afford 0.082 g (42% yield) of2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-5-yl)ethan-1-olas a colorless solid.

To a solution of2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-5-yl)ethan-1-ol(0.082 g, 0.26 mmol) in acetonitrile (5 mL) was added1-(azetidin-3-ylmethyl)pyrrolidine dihydrochloride (0.082 g, 0.39 mmol)followed by TEA (0.14 mL, 1.0 mmol). The reaction was then heated to 50°C. until the reaction was complete. The mixture was diluted with waterand extracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (TEA:MeOH:EtOAc:Hex5:1:25:75 to 5:10:25:75) to afford 0.10 g (88% yield) of TRV1597 as ayellow solid. ¹H NMR (DMSO, 400 MHz) δ=8.06 (s, 1H), 7.67 (s, 1H), 7.54(d, J=5.77 Hz, 1H), 6.51 (s, 1H), 5.74 (pentet, J=6.40 Hz, 1H), 4.41 (t,J=8.28 Hz, 2H), 3.98 (dd, J₁=5.77 Hz, J₂=8.28 Hz, 2H), 3.00 (septet,J=6.71 Hz, 1H), 2.72 (d, J=7.53 Hz, 2H), 2.48-2.38 (m, 4H), 1.74-1.61(m, 4H).

A reaction vial was charged with6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(1.20 g, 3.40 mmol), (3-formylphenyl)boronic acid (0.63 g, 4.25 mmol),Pd(PPh₃)₄ (0.20 g, 0.17 mmol). After degassed and refilled withnitrogen, the vial was charged with dioxane (10 mL) and aq. Na₂CO₃ (6mL, 2.0 M, 12.0 mmol). The reaction vial was further re-degassed,refilled with nitrogen, sealed, and then heated to 100° C. until thereaction was complete. The mixture was diluted with water, added 5 mL of2N NaOH, and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:0:15:75 to 5:2:15:75) to afford 1.20 g (93% yield)of3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzaldehydeas red oil.

A solution of3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzaldehyde(0.26 g, 0.69 mmol) in THF (5 mL) was cooled in an ice-water bath. Tothe cooled solution was added sodium borohydride (0.040 g dissolved in 2mL of 1N aq. NaOH, 1.06 mmol) slowly. The reaction mixture was stirreduntil it was complete, then quenched with 1N aq. HCl, basified with 1NNaOH, and then extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 5:0:25:75 to 5:5:25:75) to afford 0.086 g (80%yield) of TRV1598 as a brown solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.64 (s,1H), 7.56 (d, J=7.53 Hz, 1H), 7.47 (t, J=7.53 Hz, 1H), 7.43 (d, J=7.53Hz, 1H), 7.16 (s, 1H), 6.07 (s, 1H), 4.80 (s, 2H), 4.44 (t, J=8.16 Hz,2H), 4.02 (dd, J₁=5.52 Hz, J₂=8.53 Hz, 2H), 3.73 (t, J=4.65 Hz, 4H),3.09 (septet, J=6.59 Hz, 1H), 2.72 (d, J=7.53 Hz, 2H), 2.47 (t, J=4.27Hz, 4H), 1.90 (broad, 1H).

n-BuLi (0.64 ml, 2.5 M, 1.6 mmol) was added dropwise to a solution ofTRV1470 (435 mg, 1.23 mmol) in THF (10 ml) at −78° C. under nitrogenatmosphere. After the mixture was stirred for 10 minutes, methyl iodide(0.153 ml, 2.46 mmol) was added to a solution, and the mixture wasstirred for 1 h at −78° C. The reaction was quenched by MeOH (1 ml), andEtOAc (50 ml) was added to the solution. The mixture was washed with 1 NNaOH and brine. The organic layer was dried and concentrated. Theresidue was purified via gradient elution (5:100:500, TEA/EtOAc/Hexaneto 2:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford6-methyl-4-(3-(morpholinomethyl)azetidin-1-yl) benzo[c][1,2,5]oxadiazoleTRV1599 (205 mg, 57%) as a red solid. ¹H NMR (400 MHz, CDCl₃): 2.35 (s,1H), 2.46-2.49 (m, 4H), 2.70 (d, J=7.6, 2H), 3.02-3.09 (m, 1H),3.72-3.74 (m, 4H), 3.94 (d-d, J=5.6, J=8.4, 2H), 4.37 (t, J=8.2, 2H),5.68 (s, 1H), 6.79 (s, 1H).

NaH (52 mg, 1.32 mmol) was added to a solution of TRV1571 (200 mg, 0.658mmol) in THF (10 ml) at 0° C. Then methyl iodide (0.122 ml, 3.0 mmol)was added to a solution, and the mixture was stirred for 5 h from 0° C.to room temperature. After the completion, the reaction was quenched byEtOAc/H₂O (1:1, 50 ml). The mixture was washed with 1 N NaOH and brine.The organic layer was dried and concentrated. The residue was purifiedvia gradient elution (5:100:500, TEA/EtOAc/Hexane to 2:5:100:500MeOH/TEA/EtOAc/Hexane) to afford6-(methoxymethyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazoleTRV1600 (170 mg, 81%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):2.46-2.48 (m, 4H), 2.70 (d, J=7.6, 2H), 3.03-3.09 (m, 1H), 3.44 (s, 3H),3.72-3.74 (m, 4H), 3.97 (d-d, J=5.6, J=8.3, 2H), 4.38-4.42 (m, 4H), 5.83(s, 1H), 6.97 (s, 1H).

(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)oxazol-4-yl)methanol (0.150 g,0.64 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloride salt(0.218 g, 0.95 mmol) were dissolved in acetonitrile (5 ml) at roomtemperature, triethylamine (0.3 ml, 1.92 mmol) was added and mixture washeated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give(2-(7-(3-(morpholinomethyl) azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)oxazol-4-yl)methanol TRV1606. Purificationwas done on ISCO flash chromatography using dichloromethane:methanol(95:5) solvent system to obtain TRV 1606 (0.210 g, 86%) as orange colorsolid. 1H NMR (CDCl3, 400 MHz): δ 7.72 (s, 1H), 7.67 (s, 1H), 6.52 (s,1H), 4.71 (s, 2H), 4.48 (t, J=8.0 Hz, 2H), 4.06 (t, J=4.0, 8.0 Hz, 2H),3.75 (m, 4H), 3.11 (m, 1H), 2.73 (d, J=8.0 Hz, 2H), 2.48 (m, 4H)

(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)oxazol-5-yl)methanol (0.236 g,1.0 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloride salt(0.343 g, 1.5 mmol) were dissolved in acetonitrile (5 ml) at roomtemperature, triethylamine (0.4 ml, 3.0 mmol) was added and mixture washeated at 80° C. for 6 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeproduct. Purification was done on ISCO flash Chromatography system usingdichloromethane:methanol (95:5) solvent system to obtain(2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)oxazol-5-yl)methanol TRV1607 (0.260 g,70%) as orange color solid. 1H NMR (CDCl3, 400 MHz): δ 7.65 (s, 1H),7.18 (s, 1H), 6.48 (s, 1H), 4.79 (s, 2H), 4.47 (t, J=8.0 Hz, 2H), 4.05(t, J=8.0 Hz, 2H), 3.75 (m, 4H), 3.12 (m, 1H), 2.73 (d, J=8.0 Hz, 2H),2.48 (m, 4H).

2-(7-(3-(morpholinomethyl)azetidin-1-yl) benzo[c][1,2,5]oxadiazol-5-yl)oxazole-4-carbaldehyde (0.08 g, 0.217 mmol) was dissolved in THF (5 mL)and cooled in an ice bath. CF3TMS (0.062 g, 0.434 mmol) was added andthen the catalyst TBAF (0.05 mL, 1.0 M solution in THF) was added. After30 minutes the reaction was removed from the ice bath and allowed towarm to room temperature. Once complete by TLC, recooled to 0° C. and 2N HCl (aq) was added, stirred for 40 minutes and then basified with 2NNaOH. This mixture was extracted with EtOAc. The combined extracts werewashed with water (2×), brine, filtered and concentrated. The crudematerial was purified via chromatography (hexane:ethylacetate:MeOH:Et3N, 5:1:0.3:0.3) to afford 0.07 mg (75%) of2,2,2-trifluoro-1-(2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)oxazol-4-yl)ethan-1-olTRV 1608 as red solid. 1H NMR (CDCl3, 400 MHz): δ 7.85 (s, 1H), 7.69 (s,1H), 6.50 (s, 1H), 5.16 (m, 1H), 4.51 (t, J=8.0 Hz, 2H), 4.09 (t, J=8.0Hz, 2H), 3.75 (m, 4H), 3.15 (m, 1H), 2.74 (d, J=4.0 Hz, 2H), 2.49 (m,4H).

3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)benzamide (0.102 g, 0.4 mmol)and 1-(azetidin-3-ylmethyl) pyrrolidine hydrochloride salt (0.128 g, 0.6mmol) were dissolved in NMP (5 ml) at room temperature, triethylamine(0.22 ml, 1.6 mmol) was added and mixture was heated at 80° C. for 2 h.After completion of reaction by TLC it was quenched with Na2CO3 (2M) andextracted with EtOAC to give crude product. Purification was done onISCO flash chromatography system using dichloromethane:methanol (90:10)solvent system to obtain 3-(7-(3-(pyrrolidin-1-ylmethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzamide TRV1609 (0.118 g, 78%) as orangecolor solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.22 (s, 1H), 8.16 (s, 1H),7.94 (m, 2H), 7.60 (0=8.0 Hz, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 6.32 (s,1H), 4.42 (t, J=8.0 Hz, 2H), 4.0 (t, J=8.0 Hz, 2H), 3.02 (m, 1H), 2.73(d, J=8.0 Hz, 2H), 2.45 (m, 4H), 1.68 (m, 4H).

4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl) benzamide (0.102 g, 0.4 mmol)and 4-(azetidin-3-ylmethyl) morpholine hydrochloride salt (0.137 g, 0.6mmol) were dissolved in NMP (5 ml) at room temperature, triethylamine(0.22 ml, 1.6 mmol) was added and mixture was heated at 80° C. for 2 h.After completion of reaction by TLC it was quenched with Na2CO3 (2M) andextracted with EtOAC to give crude. Purification was done on ISCO flashChromatography system using dichloromethane:methanol (95:5) solventsystem to obtain 4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)benzamide TRV1610 (0.068 g, 51%) as yellowsolid. ¹H NMR (DMSO-d6, 400 MHz): δ 8.08 (s, 1H), 7.99 (s, 1H), 7.97 (s,1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 6.31 (s,1H), 4.41 (t, J=8.0 Hz, 2H), 3.99 (m, 2H), 3.58 (m, 4H), 308 (m, 1H),2.64 (d, J=8.0 Hz, 2H), 2.39 (m, 4H).

H₂O₂ (30% in H₂O, 2.65 ml) was added dropwise to a solution of4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(700 mg, 2.65 mmol) and NaOH (1 N, 2.65 ml) in EtOH (10 ml) at roomtemperature. After the mixture was stirred for 20 minutes, the reactionwas quench with HCl (1 N) and pH was adjusted to 2. The reaction mixturewas concentrated, and 20 ml of EtOAc was added to the residue. Themixture was then washed with brine. The organic layer was dried andconcentrated. The residue was purified via gradient elution (1:10,EtOAc/Hexane to 1:5 EtOAc/Hexane) to afford7-fluorobenzo[c][1,2,5]oxadiazol-5-ol (330 mg, 81%) as a pale yellowsolid.

MeI (0.25 ml, 4 mmol) was added to a suspension solution of7-fluorobenzo[c][1,2,5]oxadiazol-5-ol (154 mg, 1.0 mmol) and K₂CO₃ (276mg, 2.0 mmol) in MeCN (10 ml) at room temperature. After the mixture wasstirred overnight, the reaction was concentrated to dry. The residue wasadded another batch of K₂CO₃ (518 mg, 3.75 mmol),4-(azetidin-3-ylmethyl) morpholine 2HCl salt (344 mg, 1.5 mmol) and 10ml of MeCN. The mixture was heated to 55° C. for 6 hours. After themixture was cooled to room temperature, EtOAc (30 ml) was added to thesolution. The mixture was washed with brine. The organic layer was driedand concentrated. The residue was purified via gradient elution(2:100:500, TEA/EtOAc/Hexane to 3:2:100:500 MeOH/TEA/EtOAc/Hexane) toafford6-methoxy-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazoleTRV1611 (210 mg, 69%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):2.44-2.46 (m, 4H), 2.68 (d, J=7.5, 2H), 2.98-3.06 (m, 1H), 3.69-3.72 (m,4H), 3.84 (s, 3H), 3.89 (d-d, J=5.5, J=8.3, 2H), 4.33 (t, J=8.2, 2H),5.51 (d, J=1.3, 1H), 6.20 (d, J=1.8, 1H). and5-methoxy-4-methyl-7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazoleTRV1613 (45 mg, 14%) as a red solid. ¹H NMR (400 MHz, CDCl3): 2.32 (s,3H), 2.46-2.48 (m, 4H), 2.70 (d, J=7.5, 2H), 3.03-3.09 (m, 1H),3.72-3.74 (m, 4H), 3.90 (s, 3H), 3.93 (d-d, J=5.5, J=8.0, 2H), 4.36 (t,J=8.0, 2H), 5.73 (s, 1H).

n-BuLi (1.0 ml, 2.5 M, 2.5 mmol) was added dropwise to a solution ofTRV1470 (706 mg, 2.0 mmol) in THF (20 ml) at −78° C. under nitrogenatmosphere. After the mixture was stirred for 10 minutes, dimethyldisulfide (0.233 ml, 2.5 mmol) was added to a solution, and the mixturewas stirred for 1 h at −78° C. The reaction was quenched by MeOH (1 ml),and

EtOAc (50 ml) was added to the solution. The mixture was washed with 1 NNaOH and brine. The organic layer was dried and concentrated. Theresidue was purified via gradient elution (5:100:500, TEA/EtOAc/Hexaneto 2:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford6-(methylthio)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1612 (550 mg, 86%) as a red brown solid. ¹HNMR (400 MHz, CDCl₃): 2.46-2.49 (m, 4H), 2.53 (s, 3H), 2.69 (d, J=7.5,2H), 3.02-3.09 (m, 1H), 3.72-3.74 (m, 4H), 3.95 (d-d, J=5.5, J=8.4, 2H),4.38 (t, J=8.2, 2H), 5.66 (s, 1H), 6.61 (s, 1H).

For experimental details see [00822] and [00823]

A reaction vial was charged with6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(0.44 g, 1.25 mmol), (2-(dimethylcarbamoyl)phenyl)boronic acid (0.30 g,1.55 mmol), Pd(PPh₃)₄ (0.072 g, 0.063 mmol). After degassed and refilledwith nitrogen, the vial was charged with dioxane (7.5 mL) and aq. Na₂CO₃(3 mL, 2.0 M, 6.0 mmol). The reaction vial was further re-degassed,refilled with nitrogen, sealed, and then heated to 90° C. until thereaction was complete. The mixture was diluted with water, added 3 mL of2N NaOH, and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(TEA:MeOH:EtOAc:Hex 2:0:15:75 to 2:5:15:75) to afford 0.52 g (100%yield) of TRV1615 as an orange solid. ¹H NMR (CDCl₃, 400 MHz)δ=7.52-7.37 (m, 4H), 7.03 (s, 1H), 6.01 (s, 1H), 4.40 (t, J=8.16 Hz,2H), 3.98 (dd, J₁=5.65 Hz, J₂=8.41 Hz, 2H), 3.72 (t, J=4.65 Hz, 4H),3.06 (septet, J=6.65 Hz, 1H), 2.94 (s, 3H), 2.70 (d, J=7.53 Hz, 2H),2.65 (s, 3H), 2.46 (t, J=4.27 Hz, 4H).

TRV1470 (0.4179 g, 1.18 mmol) and (4-(methoxycarbonyl) phenyl) boronicacid (0.2772 g, 1.54 mmol) were massed into a tube. The tube wasevacuated and purged with argon (3×). DME (2.7 mL) and aqueous Na₂CO₃(1.8 mL, 2N aq solution) was added to the tube. The tube was degassedfor 5 minutes by bubbling argon gas through the solution. Pd (PPh₃)₄(0.069 g, 0.06 mmol) was added all at once, the tube was sealed andheated to 95° C. for 16 hours. The reaction was then cooled to roomtemperature and diluted with DCM and water. The layers were separatedand the aqueous layer was back-extracted with DCM (2×). The combinedorganic layers were washed with water, dried (MgSO₄), filtered andconcentrated to give a crude brown solid. This crude material waspurified via flash chromatography (60% EtOAc/hexane with 5% TEAadditive) to afford 0.4752 g (99% yield) methyl ester 5. This materialwas dissolved in THF (15 mL) and cooled to 0° C. MeMgBr (1.2 mL, 3.0 Msolution in Et₂O) was added dropwise and the reaction was allowed towarm to room temperature overnight. The reaction was then recooled andquenched with saturated ammonium chloride. This was extracted with EtOAc(3×) and the combined organic layers were washed with water, brine,dried (MgSO₄), filtered and concentrated to give the crude alcohol. Thecrude material was purified via chromatography (60% EtOAc/hexane with 5%TEA additive) to afford 0.2202 g (46% yield) of TRV1616. ¹H NMR (500MHz, DMSO) δ=7.70 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.29 (s,1H), 6.26 (s, 1H), 5.06 (s, 1H), 4.37 (t, J=8.0 Hz, 2H), 3.97-3.94 (m,2H), 3.57 (t, J=4.5 Hz, 4H), 3.09-3.01 (m, 1H), 2.62 (d, J=7.5 Hz, 2H),2.38 (br s, 4H), 1.45 (s, 6H).

TRV1470 (0.4044 g, 1.14 mmol) and (3-(methoxycarbonyl) phenyl) boronicacid (0.2664 g, 1.48 mmol) were massed into a tube. The tube wasevacuated and purged with argon (3×). DME (2.6 mL) and aqueous Na₂CO₃(1.7 mL, 2N aq solution) was added to the tube. The tube was degassedfor 5 minutes by bubbling argon gas through the solution. Pd (PPh₃)₄(0.069 g, 0.06 mmol) was added all at once, the tube was sealed andheated to 95° C. for 16 hours. The reaction was then cooled to roomtemperature and diluted with DCM and water. The layers were separatedand the aqueous layer was back-extracted with DCM (2×). The combinedorganic layers were washed with water, dried (MgSO₄), filtered andconcentrated to give a crude brown solid. This crude material waspurified via flash chromatography (70% EtOAc/hexane with 5% TEAadditive) to afford 0.4769 g (99% yield) methyl ester. This material wasdissolved in THF (15 mL) and cooled to 0° C. MeMgBr (1.2 mL, 3.0 Msolution in Et₂O) was added dropwise and the reaction was allowed towarm to room temperature overnight. The reaction was then recooled andquenched with saturated ammonium chloride. This was extracted with EtOAc(3×) and the combined organic layers were washed with water, brine,dried (MgSO₄), filtered and concentrated to give the crude alcohol. Thecrude material was purified via chromatography (60% EtOAc/hexane with 5%TEA additive) to afford 0.2507 g (53% yield) of TRV1617. ¹H NMR (500MHz, DMSO) δ=7.82 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz,1H), 7.41 (t, J=8.0 Hz, 1H), 7.27 (s, 1H), 6.23 (s, 1H), 5.08 (s, 1H),4.38 (t, J=8.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.57 (t, J=4.5 Hz, 4H),3.10-3.01 (m, 1H), 2.63 (d, J=7.5 Hz, 2H), 2.38 (br s, 4H), 1.48 (s,6H).

2,2,2-trifluoro-1-(5-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-2-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeTRV-1618. Purification was done on ISCO flash chromatography systemusing dichloromethane:methanol (95:5) as solvent to obtain2,2,2-trifluoro-1-(5-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pyridin-2-yl)ethan-1-olTRV1618 (0.115 g, 85%) as orange color solid. ¹H NMR (DMSO-d6, 400 MHz):δ 9.0 (s, 1H), 8.32 (dd, J=4.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.47 (m,1H), 7.15 (d, J=8.0 Hz, 1H), 6.33 (s, 1H), 5.24 (m, 1H), 4.41 (t, J=8.0Hz, 2H), 3.98 (t, J=8.0 Hz, 2H), 3.57 (m, 4H), 3.10 (m, 1H), 2.64 (d,J=4.0 Hz, 2H), 2.38 (m, 4H).

2,2,2-trifluoro-1-(6-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-2-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeTRV-1569. Purification was done on ISCO flash chromatography systemusing dichloromethane:methanol (95:5) as solvent to obtain2,2,2-trifluoro-1-(6-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pyridin-2-yl)ethan-1-olTRV1619 (0.105 g, 80%) as orange color solid. ¹H NMR (DMSO-d6, 400 MHz):δ 8.18 (d, J=8.0 Hz, 1H), 8.06 (t, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.68 (d,J=8.0 Hz, 1H), 7.12 (d, J=4.0 Hz, 1H), 6.78 (s, 1H), 5.33 (m, 1H), 4.38(t, J=8.0 Hz, 2H), 3.97 (t, J=8.0 Hz, 2H), 3.58 (m, 4H), 3.10 (m, 1H),2.64 (d, J=4.0 Hz, 2H), 2.38 (m, 4H).

2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-4-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeTRV-1569. Purification was done on ISCO flash chromatography systemusing dichloromethane:methanol (95:5) as solvent to obtain2,2,2-trifluoro-1-(2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pyridin-4-yl)ethan-1-olTRV1620 (0.110 g, 82%) as orange color solid. ¹H NMR (DMSO-d6, 400 MHz):δ 8.78 (d, J=4.0 Hz, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.58 (d, J=4.0 Hz,1H), 7.23 (d, J=4.0 Hz, 1H), 6.74 (s, 1H), 5.39 (m, 1H), 4.42 (t, J=8.0Hz, 2H), 3.99 (t, J=8.0 Hz, 2H), 3.58 (m, 4H), 3.09 (m, 1H), 2.65 (d,J=4.0 Hz, 2H), 2.39 (m, 4H).

2,2,2-trifluoro-1-(5-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeTRV-1569. Purification was done on ISCO flash chromatography systemusing dichloromethane:methanol (95:5) as solvent to obtain2,2,2-trifluoro-1-(5-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-olTRV-1621 (0.099 g, 75%) as orange color solid. ¹H NMR (DMSO-d6, 400MHz): δ 9.04 (d, J=4.0 Hz, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 7.42 (s, 1H)7.21 (d, J=8.0 Hz, 1H), 6.27 (s, 1H), 5.43 (m, 1H), 4.98 (d, J=8.0 Hz,1H), 4.43 (t, J=8.0 Hz, 2H), 4.01 (t, J=8.0 Hz, 2H), 3.57 (m, 4H), 3.11(m, 1H), 2.64 (d, J=4.0 Hz, 2H), 2.39 (m, 4H).

2,2,2-trifluoro-1-(6-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-ol(0.1, 0.32 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeTRV-1569. Purification was done on ISCO flash chromatography systemusing dichloromethane:methanol (95:5) as solvent to obtain2,2,2-trifluoro-1-(6-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)pyridin-3-yl)ethan-1-olTRV1622 (0.095 g, 73%) as orange color solid. ¹H NMR (DMSO-d6, 400 MHz):δ 8.80 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (s,1H), 7.19 (s, 1H), 6.77 (s, 1H), 5.41 (m, 1H), 4.43 (m, 2H), 4.02 (m,2H), 3.96 (m, 4H), 3.10 (m, 1H), 2.64 (d, J=4.0 Hz, 2H), 2.38 (m, 4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.35 g, 1.34 mmol), 1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethan-1-ol(0.28 g, 1.07 mmol), Pd(PPh₃)₄ (0.090 g, 0.080 mmol). After degassed andrefilled with nitrogen, the vial was charged with dioxane (5 mL) and aq.Na₂CO₃ (3 mL, 2.0 M, 6.0 mmol). The reaction vial was furtherre-degassed, refilled with nitrogen, sealed, and then heated to 90° C.until the reaction was complete. The mixture was diluted with water,added 3 mL of 2N NaOH, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:Hex 0:100 to 20:80) to afford 0.20 g (60% yield) of2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-5-yl)ethan-1-olas a colorless solid.

2,2,2-Trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-5-yl)ethan-1-ol(0.20 g, 0.64 mmol) obtained above and 4-(azetidin-3-ylmethyl)morpholinedihydrochloride (0.23 g, 1.00 mmol) was suspended in MeCN (5 mL). To thesuspension was added TEA (0.35 mL, 2.55 mmol). The resultant solutionwas heated to 50° C. overnight, cooled to room temperature, diluted withethyl acetate, and washed with brine. The organic phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (MeOH:DCM 0:100 to 5:95) toafford 0.25 g (86% yield) of TRV1625 as an orange solid. ¹H NMR (CDCl₃,400 MHz) δ=8.06 (s, 1H), 7.67 (s, 1H), 7.55 (d, J=5.77 Hz, 1H), 6.51 (s,1H), 5.74 (pentet, J=6.60 Hz, 1H), 4.40 (t, J=8.15 Hz, 2H), 3.97 (t,J=6.90 Hz, 2H), 3.57 (t, J=4.27 Hz, 4H), 3.07 (septet, J=6.65 Hz, 1H),2.63 (d, J=7.53 Hz, 2H), 2.44-2.33 (m, 4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.29 g, 1.10 mmol), 2-bromothiazole-4-carbaldehyde (0.19 g, 1.00 mmol),XPhos Pd G2 (0.024 g, 0.030 mmol). The vial was degassed and refilledwith nitrogen. To the vial was added dioxane (3 mL) and aq. K₃PO₄ (3.3mL, 0.62 M, 2.05 mmol). The reaction vial was re-degassed, refilled withnitrogen, sealed, and then heated to 60° C. for 24 h. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography usinggradient elution (EtOAc:Hex 0:100 to 20:80) to afford 0.120 g (48%yield) of2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-4-carbaldehyde as acolorless solid.

2-(7-Fluorobenzo[c][1,2,5]oxadiazol-5-yl) thiazole-4-carbaldehyde (0.22g, 0.88 mmol) and trimethyl (trifluoromethyl) silane (0.20 mL, 1.30mmol) was dissolved in anhydrous THF (7.5 mL). The solution was cooledin an ice-water bath before TBAF (0.080 mL, 1M, 0.080 mmol) was dropwiseadded. The resultant dark solution was stirred at ice-water bathtemperature until it was complete, and then quenched with 2N aq. HCl.The reaction mixture was warmed to room temperature, stirred for 0.5 h,then diluted with water, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:DCM:Hex 0:30:50 to 20:30:50) to afford 0.060 g (21% yield) of 2,2, 2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-4-yl) ethan-1-ol as a white solid.

To a solution of2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-4-yl)ethan-1-ol(0.060 g, 0.19 mmol) in acetonitrile (5 mL) was added1-(azetidin-3-ylmethyl)morpholine dihydrochloride (0.060 g, 0.26 mmol)followed by TEA (0.10 mL, 0.72 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution (MeOH:DCM 0:100to 5:100) to afford 0.065 g (76% yield) of TRV1626 as an orange solid.¹H NMR (DMSO, 400 MHz) δ=7.98 (s, 1H), 7.66 (s, 1H), 7.09 (d, J=6.27 Hz,1H), 6.49 (s, 1H), 5.40 (pentet, J=6.90 Hz, 1H), 4.41 (t, J=8.15 Hz,2H), 3.98 (dd, J₁=6.02 Hz, J₂=8.03 Hz, 2H), 3.57 (t, J=4.40 Hz, 4H),3.07 (septet, J=6.65 Hz, 1H), 2.64 (d, J=7.53 Hz, 2H), 2.44-2.34 (m,4H).

A reaction vial was charged with4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(0.58 g, 2.20 mmol), 4-bromothiazole-2-carbaldehyde (0.38 g, 2.00 mmol),XPhos Pd G2 (0.047 g, 0.060 mmol). The vial was degassed and refilledwith nitrogen. To the vial was added dioxane (6.5 mL) and aq. K₃PO₄ (6.5mL, 0.62 M, 4.00 mmol). The reaction vial was re-degassed, refilled withnitrogen, sealed, and then heated to 60° C. for 24 h. The mixture wasdiluted with water, added 3 mL of 2N NaOH, and extracted with ethylacetate. The ethyl acetate phase was dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash chromatography usinggradient elution (EtOAc:Hex 0:100 to 10:90) to afford 0.36 g (72% yield)of 4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl) thiazole-2-carbaldehyde asa colorless solid.

4-(7-Fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-2-carbaldehyde (0.36g, 1.44 mmol) and trimethyl(trifluoromethyl)silane (0.35 mL, 2.28 mmol)was dissolved in anhydrous THF (10 mL). The solution was cooled in anice-water bath before TBAF (0.15 mL, 1M, 0.15 mmol) was dropwise added.The resultant dark solution was stirred at ice-water bath temperatureuntil it was complete, and then quenched with 2N aq. HCl. The reactionmixture was warmed to room temperature, stirred for 0.5 h, then dilutedwith water, and extracted with ethyl acetate. The ethyl acetate phasewas dried over anhydrous sodium sulfate and concentrated. The residuewas purified by flash chromatography using gradient elution(EtOAc:DCM:Hex 0:30:50 to 20:30:50) to afford 0.050 g (11% yield) of 2,2,2-trifluoro-1-(4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-2-yl)ethan-1-olas a white solid.

To a solution of2,2,2-trifluoro-1-(4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazol-2-yl)ethan-1-ol(0.050 g, 0.16 mmol) in acetonitrile (5 mL) was added1-(azetidin-3-ylmethyl)morpholine dihydrochloride (0.045 g, 0.20 mmol)followed by TEA (0.080 mL, 0.58 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution (MeOH:DCM 0:100to 5:100) to afford 0.060 g (84% yield) of TRV1627 as an orange solid.¹H NMR (DMSO, 400 MHz) δ=8.57 (s, 1H), 7.94 (d, J=6.02 Hz, 1H), 7.65 (s,1H), 6.60 (s, 1H), 5.67 (pentet, J=6.65 Hz, 1H), 4.38 (t, J=7.78 Hz,2H), 3.96 (dd, J₁=6.27 Hz, J₂=8.03 Hz, 2H), 3.58 (t, J=4.15 Hz, 4H),3.07 (septet, J=6.75 Hz, 1H), 2.64 (d, J=7.53 Hz, 2H), 2.44-2.34 (m,4H).

CuCN (594 mg, 6.6 mmol) and TRV1470 (1.06 g, 3.0 mmol) were added to dryNMP (8 ml). The vial was purged with nitrogen for several times. Themixture was heated to 150° C. and stirred for 10 hours. After completionchecked by TLC, the reaction was quenched with aqueous ammonia hydroxide(5 ml), and EtOAc (50 ml) was added to the solution. The mixture waswashed with 1 N NaOH and brine. The organic layer was dried andconcentrated. The residue was purified via gradient elution (5:100:500,TEA/EtOAc/Hexane to 2:5:100:500 MeOH/TEA/EtOAc/Hexane) to affordTRV-1570 (708 mg, 79%) as a red solid.

Hydroxylamine hydrochloride (167 mg, 2.4 mmol) and sodium hydroxide (96mg, 2.4 mmol) were added to a solution of TRV-1570 (598 mg, 2 mmol) inmethanol at room temperature. The reaction mixture was stirred for twodays at room temperature. Solvent was evaporated and the residue wasused for the next step without purification.

N,N-Diisopropylethylamine (0.9 mL, 5.2 mol) was added toN-hydroxy-7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carboximidamide(664 mg, 2.0 mol) in DMF (15 mL) at room temperature under nitrogen. Themixture was cooled to 0° C. and ethyl oxalyl chloride (0.29 mL, 2.6mmol) added dropwise. After stirring at 0° C. for 10 min, the mixturewas warmed to room temperature and then to 50° C. and stirred for 3 h.The mixture was diluted with EtOAc (50 mL) and washed with brine (3×50mL). The solution was dried (Na₂SO₄) and evaporated in vacuo. Theresidue was purified via gradient elution (2:100:500, TEA/EtOAc/Hexaneto 2:2:100:500 MeOH/TEA/EtOAc/Hexane) to afford ethyl3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1,2,4-oxadiazole-5-carboxylate(397 mg, 48%) as red oil.

MeMgBr (0.50 ml, 1.5 mmol) was added to a solution of ethyl3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1,2,4-oxadiazole-5-carboxylate(200 mg, 0.48 mmol) THF (10 ml) at 0° C. After the mixture was stirred 2h, the reaction was quenched by EtOAc/H₂O (1:1, 50 ml). The mixture waswashed with brine. The organic layer was dried and concentrated. Theresidue was purified via gradient elution (2:100:500, TEA/EtOAc/Hexaneto 3:2:100:500 MeOH/TEA/EtOAc/Hexane) to afford TRV1628 (130 mg, 67%) asa red solid. ¹H NMR (400 MHz, CDCl3): 1.71 (s, 6H), 2.47-2.49 (m, 4H),2.72 (d, J=7.5, 2H), 3.05-3.11 (m, 1H), 3.72-3.75 (m, 4H), 4.04 (d-d,J=5.5, J=8.5, 2H), 4.46 (t, J=8.3, 2H), 6.44 (s, 1H), 7.81 (s, 1H).

NaBH₄ (46 mg, 1.21 mmol) was added to a solution of ethyl3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1,2,4-oxadiazole-5-carboxylate(250 mg, 0.604 mmol) in THF (10 ml) at 0° C. After the mixture wasstirred 2 h, the reaction was quenched by EtOAc/H₂O (1:1, 50 ml). Themixture was washed with brine. The organic layer was dried andconcentrated. The residue was purified via gradient elution (2:100:500,TEA/EtOAc/Hexane to 3:2:100:500 MeOH/TEA/EtOAc/Hexane) to afford3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1,2,4-oxadiazol-5-yl)methanolTRV1629 (40 mg, 18%) as a red solid. ¹H NMR (400 MHz, CDCl3): 2.48-2.50(m, 4H), 2.73 (d, J=7.3, 2H), 3.06-3.11 (m, 1H), 3.73-3.75 (m, 4H), 4.03(d-d, J=5.6, J=8.4, 2H), 4.46 (t, J=8.3, 2H), 4.99 (s, 2H), 6.44 (s,1H), 7.79 (s, 1H).

2,2,2-trifluoro-1-(3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)pyridin-2-yl)ethan-1-ol(0.1 g, 0.32 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.110 g, 0.47 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.18 ml, 1.28 mmol) was added and mixturewas heated at 80° C. for 2 h. After completion of reaction by TLC it wasquenched with Na₂CO₃ (2M) and extracted with EtOAC to give crudeproduct. Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain 2, 2,2-trifluoro-1-(3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) pyridin-4-yl) ethan-1-ol TRV1636 (0.080g, 75%) as orange color solid. ¹H NMR (DMSO-d6, 400 MHz): δ 8.74 (d,J=8.0 Hz, 1H), 8.57 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz,1H), 7.03 (s, 1H), 5.85 (s, 1H), 5.24 (m, 1H), 4.40 (m, 2H), 3.95 (m,2H), 3.56 (m, 4H), 3.09 (m, 1H), 2.64 (d, J=8.0 Hz, 2H), 2.37 (m, 4H).

TRV1470 (0.4197 g, 1.19 mmol) and 3-bromophenylboronic acid (0.2510 g,1.25 mmol) were sealed in a tube. The tube was evacuated and purged withargon (3 cycles). 2M Na₂CO₃ (1.8 mL, 2.0 M aq solution) was added alongwith DME (2.7 mL). Then Pd(PPh₃)₄ (0.0690 g, 0.059 mmol) was added allat once. The tube was re-sealed and heated to 95° C. for 5 hours. Aftercooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combine organic extracts were then washed with H₂O(3×), brine and then dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified via chromatography (50% EtOAc/hexane+5% TEA)to afford 0.3918 g (75% yield) of arylbromide 2. The arylbromide (0.3881g, 0.90 mmol) was dissolved in THF (10 mL) and cooled to −78° C. nBuLi(0.74 mL, 1.6 M solution in hexane) was added dropwise over 5 minutes.The reaction was allowed to stir for 15 minutes and then a solution of3-oxetanone (0.1042 g, 1.45 mmol) in THF (1 mL) was added dropwise. Thereaction was then stirred overnight while slowly warming to roomtemperature. Recooled in an ice bath and quenched with saturatedammonium chloride and then diluted with EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc (3×). the combinedlayers were then washed with water (2×), brine, dried (MgSO₄), filteredand concentrated. The crude material was ultimately purified with columnchromatography (70% EtOAc/hexane+5% TEA) to afford TRV1638 (0.1406 g,37% yield). ¹H NMR (DMSO, 500 MHz) δ=7.90 (s, 1H), 7.69 (d, J=7.5 Hz,2H), 7.52 (t, J=7.5 Hz, 1H), 7.32 (s, 1H), 6.41 (s, 1H), 6.25 (s, 1H),4.81-4.77 (m, 4H), 4.38 (t, J=8.5 Hz, 2H), 3.98-3.95 (m, 2H), 3.57 (t,J=4.5 Hz, 4H), 3.09-3.01 (m, 1H), 2.64 (d, J=7.5 Hz, 2H), 2.38 (br s,4H).

TRV1470 (0.4054 g, 1.15 mmol) and 4-bromophenylboronic acid (0.2430 g,1.21 mmol) were sealed in a tube. The tube was evacuated and purged withargon (3 cycles). 2M Na₂CO₃ (1.8 mL, 2.0 M aq solution) was added alongwith DME (2.7 mL). Then Pd(PPh₃)₄ (0.0670 g, 0.058 mmol) was added allat once. The tube was re-sealed and heated to 95° C. for 5 hours. Aftercooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combine organic extracts were then washed with H₂O(3×), brine and then dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified via chromatography (40% EtOAc/hexane+5% TEA)to afford 0.3273 g (66% yield) of arylbromide 1. The arylbromide (0.3054g, 0.71 mmol) was dissolved in THF (10 mL) and cooled to −78° C. nBuLi(0.50 mL, 1.6 M solution in hexane) was added dropwise over 5 minutes.The reaction was allowed to stir for 15 minutes and then a solution of3-oxetanone (0.0793 g, 1.1 mmol) in THF (1 mL) was added dropwise. Thereaction was then stirred overnight while slowly warming to roomtemperature. Recooled in an ice bath and quenched with saturatedammonium chloride and then diluted with EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc (3×). The combinedlayers were then washed with water (2×), brine, dried (MgSO₄), filteredand concentrated. The crude material was ultimately purified with columnchromatography (85% EtOAc/hexane+5% TEA) to afford TRV1639 (0.1084 g,36% yield). ¹H NMR (DMSO, 500 MHz) δ=7.82 (d, J=8.0 Hz, 2H), 7.71 (d,J=8.0 Hz, 2H), 7.33 (s, 1H), 6.42 (s, 1H), 6.28 (s, 1H), 4.80 (d, J=6.5Hz, 2H), 4.71 (d, J=6.5 Hz, 2H), 4.38 (t, J=8.0 Hz, 2H), 3.97 (t, J=8.0Hz, 2H), 3.57 (t, J=4.5 Hz, 4H) 3.09-3.01 (m, 1H), 2.63 (d, J=7.5 Hz,2H), 2.38 (br s, 4H).

Diisopropylethylamine (1.043 ml, 6.0 mmol) and trifluoroacetic anhydrous(0.42 ml, 3.0 mmol) were added separately to a solution ofN-hydroxy-7-(3-(morpholinomethyl) azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carboximidamide (500 mg, 1.50 mmol) in THF(20 ml) and DMF (30 ml) at room temperature. After the mixture wasstirred 2 h, the reaction was added with EtOAc (60 ml). The mixture waswashed with brine. The organic layer was dried and concentrated. Theresidue was purified via gradient elution (5:100:500, TEA/EtOAc/Hexaneto 3:5:100:500 MeOH/TEA/EtOAc/Hexane) to afford4-(3-(morpholinomethyl)azetidin-1-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzo[c][1,2,5]oxadiazoleTRV1643 (350 mg, 57%) as a red solid. ¹H NMR (400 MHz, CDCl₃): 2.48-2.50(m, 4H), 2.73 (d, J=7.5, 2H), 3.07-3.16 (m, 1H), 3.73-3.75 (m, 4H), 4.09(d-d, J=5.3, J=8.5, 2H), 4.51 (t, J=8.2, 2H), 6.45 (s, 1H), 7.88 (s,1H).

DCC (618 mg, 3.0 mmol) was added to a solution ofN-hydroxy-7-(3-(morpholinomethyl) azetidin-1-yl)benzo[c][1,2,5]oxadiazole-5-carboximidamide (500 mg, 1.5 mmol) and3,3,3-trifluoro-lactic acid (432 mg, 3.0 mmol) in THF (20 ml) and DMF(30 ml) at room temperature. After the mixture was stirred 3 h, thereaction was heated to 70° C. for overnight. One more equivalent of DCC(309 mg, 1.5 mmol) and 3, 3, 3-trifluoro-lactic acid (216 mg, 1.5 mmol)were added to the reaction mixture and the reaction was stirred for 8hours at this temperature. The reaction was added with EtOAc (60 ml).The mixture was washed with brine. The organic layer was dried andconcentrated. The residue was purified via gradient elution (1:99,MeOH/DCM to 3:97, MeOH/DCM) to afford2,2,2-trifluoro-1-(3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1,2,4-oxadiazol-5-yl)ethan-1-ol TRV1644 (350 mg, 53%) as an orange solid. ¹H NMR (400 MHz,CDCl₃): 2.50-2.52 (m, 4H), 2.74 (d, J=7.5, 2H), 3.07-3.14 (m, 1H),3.74-3.77 (m, 4H), 4.05 (d-d, J=5.5, J=8.5, 2H), 4.47 (t, J=8.3, 2H),5.43 (q, J=5.9, 1H), 6.41 (s, 1H), 7.82 (s, 1H).

A round-bottomed flask was charged with6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole (3.255 g, 15.0 mmol), dppp(371 mg, 0.9 mmol) and Pd(OAc)₂ (101 mg, 0.45 mmol). The flask waspurged with nitrogen for several times, and then dry DMF (30 ml), ethylacrylate (4.9 ml, 45.0 mmol) and TEA (6.26 ml, 45 mmol) were added tothe mixture separately.

The resulting mixture was then heated to 80° C. After the reaction wascompleted for 2 h, 100 ml of EtOAc was added to the mixture. The mixturewas washed with brine for 3 times. The organic layer was dried andconcentrated. The residue was purified via gradient elution (2:95,EtOAc/Hexane to 6:85 EtOAc/Hexane) to afford ethyl(E)-3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl) acrylate (3.3 g, 93%) asan orange solid.

MeMgBr (10 mg, 30 mmol) was added to a solution of afford ethyl(E)-3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl) acrylate (1.652 g, 7.0mmol) in THF (35 ml) at −5° C. After the mixture was stirred 4 h, thereaction was quenched by 3 ml of MeOH. EtOAc (80 ml) was added to themixture. The mixture was washed with saturated NH₄Cl and brine. Theorganic layer was dried and concentrated. The residue was purified viagradient elution (5:95, EtOAc/Hexane to 15:85 EtOAc/Hexane) to afford(E)-4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)-2-methylbut-3-en-2-ol (1.0g, 64%) as a light yellow solid.

TEA (0.50 ml, 3.6 mmol) was added to a solution of(E)-4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)-2-methylbut-3-en-2-ol (200mg, 0.90 mmol) and 4-(azetidin-3-ylmethyl)morpholine 2HCl salt (309 mg,1.35 mmol) in MeCN (10 ml). The mixture was heated to 70° C. for 36hours. After the mixture was cooled to room temperature, EtOAc (30 ml)was added to the solution. The mixture was washed with brine. Theorganic layer was dried and concentrated. The residue was purified viagradient elution (2:100:500, TEA/EtOAc/Hexane to 4:2:100:500MeOH/TEA/EtOAc/Hexane) to afford(E)-2-methyl-4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)but-3-en-2-olTRV1645 (230 mg, 72%) as a yellow solid. ¹H NMR (400 MHz, CDCl3): 1.46(s, 6H), 2.47-2.49 (m, 4H), 2.71 (d, J=7.3, 2H), 3.05-3.11 (m, 1H),3.72-3.75 (m, 4H), 3.97 (d-d, J=5.8, J=8.2, 2H), 4.41 (t, J=8.2, 2H),5.96 (s, 1H), 5.43 (d, J=16.1, 1H), 6.59 (d, J=16.1, 1H), 6.92 (s, 1H).

A reaction vial was charged with6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(0.71 g, 2.00 mmol),1-methyl-4-(3,3,4,4-tetramethylborolan-1-yl)-1H-pyrazole (0.47 g, 2.30mmol), Pd(PPh₃)₄ (0.070 g, 0.061 mmol). After degassed and refilled withargon, dioxane (6 mL) and aq. Na₂CO₃ (4.0 mL, 2.0 M, 8.0 mmol) wasadded. The reaction vial was further re-degassed, refilled with argon,sealed, and then heated to 90° C. until the reaction was complete. Themixture was diluted with water, added 3 mL of 2N NaOH, and extractedwith ethyl acetate. The organic phase was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flashchromatography using gradient elution (MeOH:TEA:EtOAc:Hex 0:2:25:75 to5:2:25:75) to afford 0.70 g6-(1-methyl-1H-pyrazol-4-yl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole as an orange solid (99% of yield).

A reaction vial was charged with6-(1-Methyl-1H-pyrazol-4-yl)-4-(3-(morpholinomethyl) azetidin-1-yl)benzo[c][1,2,5]oxadiazole (0.29 g, 0.82 mmol). After degassed andrefilled with argon, THF (5 mL) was added. The resultant solution wascooled to −78° C. in a dry ice bath. n-BuLi (0.40 mL, 2.5 M, 1.00 mmol)was added dropwise. After stirred for 1 h −78° C., ethyl 2, 2,2-trifluoroacetate (0.36 mL, 3.00 mmol) was added. The reaction wasstirred at −78° C. for 2 h before quenched with methanol. The mixturewas diluted with water, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(MeOH:TEA:EtOAc:Hex 0:2:25:75 to 5:2:25:75) to afford 0.20 g (55% yield)of2,2,2-trifluoro-1-(1-methyl-4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrazol-5-yl)ethan-1-oneas an orange solid.

A solution of2,2,2-trifluoro-1-(1-methyl-4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrazol-5-yl)ethan-1-one(0.050 g, 0.16 mmol) in methanol (5 mL) was cooled in an ice-water bath.Sodium borohydride (0.025 g, 0.66 mmol) was added. The reaction mixturewas warmed to rt, and stirred until it was complete. The reaction wasquenched with 1N aq. HCl, diluted with water, basified with aq. NaOH,and extracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (MeOH:TEA:EtOAc:Hex0:2:25:75 to 5:2:25:75) to afford 0.18 g (90% yield) of TRV1647 as anorange solid. ¹H NMR (CDCl₃, 400 MHz) δ=7.55 (s, 1H), 6.83 (s, 1H), 5.70(s, 1H), 5.44 (q, J=7.27 Hz, 1H), 5.08 (broad, 1H), 4.34 (t, J=8.03 Hz,1H), 4.27 (t, J=8.16 Hz, 1H), 4.14 (s, 3H), 3.96-3.86 (m, 2H), 3.71 (t,J=4.52 Hz, 4H), 3.01 (septet, J=6.90 Hz, 1H), 2.68 (d, J=7.53 Hz, 2H),2.45 (t, J=4.27 Hz, 4H).

A reaction vial was charged with6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole (0.65 g, 3.00 mmol),1-methyl-5-(3,3,4,4-tetramethylborolan-1-yl)-1H-pyrazole (0.72 g, 3.46mmol), Pd(PPh₃)₄ (0.10 g, 0.090 mmol). After degassed and refilled withargon, dioxane (8 mL) and aq. Na₂CO₃ (6.0 mL, 2.0 M, 12.0 mmol) wasadded. The reaction vial was further re-degassed, refilled with argon,sealed, and then heated to 90° C. until the reaction was complete. Themixture was diluted with water, and extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:Hex:DCM 0:50:30 to 8:50:30) to afford 0.45 g of4-fluoro-6-(1-methyl-1H-pyrazol-5-yl) benzo[c][1,2,5]oxadiazole (69% ofyield) as a colorless solid.

A solution of 4-fluoro-6-(1-methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole (0.23 g, 1.04 mmol) in DCM (5.0 mL) was cooledin an ice-water bath. Bromine (0.65 mL, 2.0 M in DCM, 1.30 mmol) wasadded slowly. The reaction mixture was slowly warmed to room temperatureand stirred until it was complete. The reaction was concentrated and thecrude product was used directly in the next step without furtherpurification.

A solution of6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-fluorobenzo[c][1,2,5]oxadiazole(0.42 g, 1.41 mmol) in acetonitrile (10 mL) was added1-(azetidin-3-ylmethyl)morpholine dihydrochloride (0.40 g, 1.75 mmol)followed by TEA (1.10 mL, 7.91 mmol). The reaction was then heated to50° C. until the reaction was complete. The mixture was diluted withwater and extracted with ethyl acetate. The ethyl acetate phase wasdried over anhydrous sodium sulfate and concentrated. The residue wasused directly in the next step without further purification.

A reaction vial was charged with6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole (0.11 g, 0.25 mmol). After degassed andrefilled with argon, THF (3 mL) was added. The resultant solution wascooled to −78° C. in a dry ice bath. n-BuLi (0.13 mL, 2.5 M, 0.31 mmol)was added dropwise. After stirred for 1 h −78° C., ethyl 2, 2,2-trifluoroacetate (0.12 mL, 1.00 mmol) was added. The reaction wasstirred at −78° C. for 2 h before quenched with methanol. The mixturewas diluted with water, and extracted with ethyl acetate. The ethylacetate phase was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(MeOH:TEA:EtOAc:Hex 0:2:25:75 to 5:2:25:75) to afford 0.040 g of2,2,2-trifluoro-1-(1-methyl-5-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrazol-4-yl)ethan-1-one.

A solution of 2, 2,2-trifluoro-1-(1-methyl-5-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrazol-4-yl) ethan-1-one (0.13 g,0.28 mmol) in THF (5 mL) was cooled in an ice-water bath. Sodiumborohydride (0.016 g, 0.42 mmol) in aq. NaOH (0.80 mL, 1 M, 0.80 mmol)was added. The reaction mixture was stirred at ice-water bathtemperature until it was complete. The reaction was diluted with ethylacetate and washed with brine. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (MeOH:DCM 0:100 to 5:95) toafford 0.11 g (88% yield) of TRV1651 as an orange solid. ¹H NMR (CDCl₃,400 MHz) δ=7.75 (s, 1H), 6.98 (s, 1H), 5.68 (s, 1H), 4.84 (q, J=7.03 Hz,1H), 4.54-4.44 (m, 2H), 4.08-3.98 (m, 2H), 3.86-3.82 (m, 3H), 3.76-3.70(m, 4H), 3.11 (septet, J=6.53 Hz, 1H), 2.74 (d, J=7.28 Hz, 2H),2.52-2.45 (m, 4H).

6-(2-methoxypyridin-3-yl)-4-fluorobenzo[c][1,2,5]oxadiazole (0.150 g,0.612 mmol) and 4-(azetidin-3-yl methyl) morpholine hydrochloride salt(0.140 g, 0.612 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.3 ml, 1.85 mmol) was added and mixture washeated at 50° C. overnight. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeproduct. Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain6-(2-methoxypyridin-3-yl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1658 (0.208 g, 90%) as red color solid. ¹HNMR (CDCl₃, 400 MHz): δ 8.23 (d, J=4.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H)7.14 (s, 1H), 7.02 (m, 1H), 6.02 (s, 1H), 4.44 (t, J=8.0 Hz, 2H), 4.05(s, 3H), 3.98 (m, 2H), 3.74 (m, 4H), 3.11 (m, 1H), 2.73 (d, J=8.0 Hz,2H), 2.48 (m, 4H)

6-(2-methoxypyridin-4-yl)-4-fluorobenzo[c][1,2,5]oxadiazole (0.150 g,0.612 mmol) and 4-(azetidin-3-yl methyl) morpholine hydrochloride salt(0.140 g, 0.612 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.3 ml, 1.85 mmol) was added and mixture washeated at 50° C. overnight. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeproduct. Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain6-(2-methoxypyridin-4-yl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1659 (0.2180 g, 92%) as red color solid. ¹HNMR (CDCl₃, 400 MHz): δ 8.26 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.12 (d,J=8.0 Hz, 1H), 6.96 (s, 1H), 5.99 (s, 1H), 4.47 (t, J=8.0 Hz, 2H), 4.05(m, 2H), 4.01 (s, 3H), 3.74 (m, 4H), 3.14 (m, 1H), 2.73 (d, J=4.0 Hz,2H), 2.48 (m, 4H).

6-(4-cyclopropyl-3-methoxyphenyl)-4-fluorobenzo[c][1,2,5]oxadiazole(0.142 g, 0.5 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.114 g, 0.5 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.2 ml, 1.5 mmol) was added and mixture washeated at 50° C. overnight. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeproduct.

Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain6-(4-cyclopropyl-3-methoxyphenyl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1660 (0.1780 g, 85%) as orange color solid.¹H NMR (CDCl₃, 400 MHz): δ 7.30 (s, 1H), 7.08 (s, 1H), 7.05 (d, J=8.0Hz, 1H), 7.0 (s, 1H), 5.96 (s, 1H), 4.42 (t, J=8.0 Hz, 2H), 3.99 (m,2H), 3.85 (s, 3H), 3.74 (m, 4H), 3.10 (m, 1H), 2.72 (d, J=8.0 Hz, 2H),2.47 (m, 4H) 1.85 (m, 1H), 1.51 (m, 2H), 1.26 (m, 2H).

TRV1470 (0.4480 g, 1.27 mmol) and 2-bromophenylboronic acid (0.2678 g,1.33 mmol) were sealed in a tube. The tube was evacuated and purged withargon (3 cycles). 2M Na₂CO₃ (1.9 mL, 2.0 M aq solution) was added alongwith DME (2.8 mL). Then Pd (PPh₃)₄ (0.0734 g, 0.064 mmol) was added allat once. The tube was re-sealed and heated to 95° C. for 5 hours. Aftercooling to room temperature, the mixture was diluted with water andEtOAc. The layers were separated and the aqueous layer was thenback-extracted. The combine organic extracts were then washed with H₂O(3×), brine and then dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified via chromatography (40% EtOAc/hexane+5% TEA)to afford 0.4642 g (85% yield) of arylbromide. This arylbromide (0.4642g, 1.08 mmol) was dissolved in THF (10 mL) and cooled to −78° C. nBuLi(0.90 mL, 1.6 M solution in hexane) was added dropwise over 5 minutes.The reaction was allowed to stir for 15 minutes and then a solution of3-oxetanone (0.1247 g, 1.73 mmol) in THF (1 mL) was added dropwise. Thereaction was then stirred overnight while slowly warming to roomtemperature. Recooled in an ice bath and quenched with saturatedammonium chloride and then diluted with EtOAc. The layers were separatedand the aqueous layer was back-extracted with EtOAc (3×). The combinedlayers were then washed with water (2×), brine, dried (MgSO₄), filteredand concentrated. The crude material was purified with columnchromatography (85% EtOAc/hexane+5% TEA) to afford TRV1663 (0.3337 g,73% yield). ¹H NMR (DMSO, 500 MHz) δ=7.46-7.38 (m, 3H), 7.30 (d, J=7.5Hz, 1H), 7.19 (s, 1H), 6.61 (br s, 1H), 6.15 (s, 1H), 4.62 (d, J=7.0 Hz,2H), 4.41 (d, J=7.0 Hz, 2H), 4.34 (t, J=8.0 Hz, 2H), 3.94-3.91 (m, 2H),3.57 (t, J=4.5 Hz, 4H), 3.07-3.01 (m, 1H), 2.63 (d, J=7.5 Hz, 2H), 2.38(br s, 4H).

DIBAl (25.76 ml, 25.76 mmol) was added to a solution of afford ethyl(E)-3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)acrylate (1.52 g, 6.44mmol) in THF (35 ml) at −5° C. After the mixture was stirred overnightat room temperature, the reaction was quenched by 3 ml of MeOH. EtOAc(40 ml) was added to the mixture. The mixture was washed with 1 N HCland brine. The organic layer was dried and concentrated. The residue waspurified via gradient elution (10:90, EtOAc/Hexane to 15:85EtOAc/Hexane) to afford(E)-3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)prop-2-en-1-ol (340 mg,28%) as a light yellow solid.

TEA (0.98 ml, 7.08 mmol) was added to a solution of(E)-3-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)prop-2-en-1-ol (340 mg,1.77 mmol) and 4-(azetidin-3-ylmethyl)morpholine 2HCl salt (608 mg, 2.66mmol) in MeCN (10 ml). The mixture was heated to 70° C. for 48 hours.After the mixture was cooled to room temperature, EtOAc (30 ml) wasadded to the solution. The mixture was washed with brine. The organiclayer was dried and concentrated. The residue was purified via gradientelution (2:100:500, TEA/EtOAc/Hexane to 4:2:100:500MeOH/TEA/EtOAc/Hexane) to afford(E)-3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)prop-2-en-1-ol(450 mg, 77%) as a yellow solid.

Dess-Martin periodinane (694 mg, 1.64 mmol) was added to a solution of(E)-3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)prop-2-en-1-ol (450 mg, 1.36 mmol) in DCM(15 ml) at room temperature. After the mixture was stirred 1 h, thereaction was quenched by saturated Sodium thiosulfate (10 ml). Themixture was washed with saturated sodium bicarbonate and brine. Theorganic layer was dried and concentrated. The residue was purified viagradient elution (2:100:500, TEA/EtOAc/Hexane to 3:2:100:500MeOH/TEA/EtOAc/Hexane) to afford (E)-3-(7-(3-(morpholinomethyl)azetidin-1-yl) benzo[c][1,2,5]oxadiazol-5-yl)acrylaldehyde (360 mg, 81%)as an orange solid.

(E)-3-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)acrylaldehyde(360 mg, 1.1 mmol) was cool to 0° C. in dry THF solution (10 ml) undernitrogen atmosphere. TMSCF₃ (0.195 ml, 1.32 mmol) and TBAF (0.22 ml,0.22 mmol, 1M solution) were added slowly to the mixture separately. Thesolution was stirred for 2 hour at 0° C. After completion checked byTLC, the mixture was added with 5 ml of water. This mixture was addedwith 50 ml of EtOAc and washed with brine. The organic layer was driedover anhydrous sodium sulphate and then concentrated. The residue waspurified via gradient elution (2:100:500, TEA/EtOAc/Hexane to4:2:100:500 MeOH/TEA/EtOAc/Hexane) to afford(E)-1,1,1-trifluoro-4-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)but-3-en-2-ol(280 mg, 64%) TRV1665 as an orange solid. ¹H NMR (400 MHz, CDCl3):2.48-2.50 (m, 4H), 2.72 (d, J=7.5, 2H), 3.06-3.12 (m, 1H), 3.73-3.75 (m,4H), 3.99 (d-d, J=5.6, J=8.2, 2H), 4.42 (t, J=8.2, 2H), 4.67-4.74 (m,1H), 5.92 (s, 1H), 6.26 (d-d, J=6.0, J=16.1, 1H), 6.86 (d, J=16.1, 1H),6.98 (s, 1H).

A 250-mL, one-necked, round-bottomed flask was charged with 45 mL of drydichloromethane and 1.60 mL (15.0 mmol) of 1,2-dimethoxyethane (DME).The solution was cooled to −30° C. and 1.50 mL (15.0 mmol) ofdiethylzinc is added. To this stirred solution was added 2.40 mL (30.0mmol) of diiodomethane over a 20 min period while maintaining thetemperature between −20° C. and −30° C. After the addition was complete,the resulting clear solution was stirred for 1 hour at −10° C. Asolution of 500 mg (2.25 mmol) of(E)-4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)-2-methylbut-3-en-2-ol in10 mL of dichloromethane was added via cannula under argon. The reactionmixture is allowed to warm to room temperature and stirred for 24 hours.After completion checked by TLC, the mixture was added with 5 ml ofwater. This mixture was washed with 1 M HCl and brine. The organic layerwas dried over anhydrous sodium sulphate and then concentrated. Theresidue was purified via gradient elution (10:90, EtOAc/Hexane to 20:80EtOAc/Hexane) to afford2-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)cyclopropyl)propan-2-ol (120mg, 23%).

TEA (0.28 ml, 2.0 mmol) was added to a solution of24247-fluorobenzo[c][1,2,5]oxadiazol-5-yl)cyclopropyl)propan-2-ol (120mg, 0.51 mmol) and 4-(azetidin-3-ylmethyl)morpholine 2HCl salt (175 mg,0.76 mmol) in MeCN (10 ml). The mixture was heated to 70° C. for 30hours. After the mixture was cooled to room temperature, EtOAc (30 ml)was added to the solution. The mixture was washed with brine. Theorganic layer was dried and concentrated. The residue was purified viagradient elution (2:25:75, TEA/EtOAc/Hexane to 4:2:25:75MeOH/TEA/EtOAc/Hexane) to afford2-(2-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)cyclopropyl)propan-2-olTRV1666 (150 mg, 79%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): ¹H NMR(400 MHz, CDCl₃): 0.93-0.98 (m, 1H), 1.07-1.24 (m, 1H), 1.32 (s, 6H),1.42-1.47 (m, 1H), 1.92-1.97 (m, 1H), 2.47 (s, br, 4H), 2.70 (d, J=7.3,2H), 3.01-3.08 (m, 1H), 3.72-3.74 (m, 4H), 3.92-3.95 (m, 2H), 4.36 (t,J=8.0, 2H), 5.59 (s, 1H), 6.67 (s, 1H).

Oxazole (0.50 mL, 7.60 mmol) was dissolved in anhydrous THF (20 mL). Thesolution was cooled in a dry ice/acetone bath. To the solution wasdropwise added n-BuLi (3.5 mL, 2.5 M, 8.8 mmol). After completeaddition, the solution was aged for 1 h at −78° C., and thentrimethylsilyl triflate (3.0 mL, 11.2 mmol) was added. The reactionmixture was naturally warmed to room temperature, quenched withsaturated ammonium chloride, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:Hex 0:100 to 5:95) to give 1.36 g of 2-triisopropylsilyloxazole(79%).

2-Triisopropylsilyloxazole (0.45 g, 2.0 mmol) was dissolved in anhydrousTHF (10 mL). The solution was cooled in a dry ice/acetone bath. To thesolution was dropwise added n-BuLi (1.0 mL, 2.5 M, 2.5 mmol). Aftercomplete addition, the solution was aged for 1 h at −78° C., and then2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.6 mL, 2.94mmol) was added. The reaction mixture was naturally warmed to roomtemperature, quenched with saturated ammonium chloride, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was used directly used in the nextstep with further purification.

A reaction vial was charged with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazoleabove, 6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole (0.70 g, 2.0 mmol), Pd(PPh₃)₄ (0.070 g, 0.060mmol). After degassed and refilled with nitrogen, the vial was chargedwith dioxane (7.5 mL) and aq. Na₂CO₃ (4.0 mL, 2.0 M, 8.0 mmol). Thereaction vial was further re-degassed, refilled with nitrogen, sealed,and then heated to 95° C. until the reaction was complete. The mixturewas diluted with water, extracted with ethyl acetate. The ethyl acetatephase was dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash chromatography using gradient elution(MeOH:TEA:EtOAc:Hex 0:2:25:75 to 1.5:2:25:75) to afford 0.60 g (61%yield for two steps) of4-(3-(morpholinomethyl)azetidin-1-yl)-6-(2-(triisopropylsilyl)oxazol-5-yl) benzo[c][1,2,5]oxadiazole as a red solid.

4-(3-(morpholinomethyl)azetidin-1-yl)-6-(2-(triisopropylsilyl)oxazol-5-yl) benzo[c][1,2,5]oxadiazole (0.48 g, 0.97 mmol) was dissolvedin anhydrous THF (7.5 mL). The solution was cooled in a dry ice/acetonebath. To the solution was dropwise added LDA (0.65 mL, 2.0 M, 1.30mmol). After complete addition, the solution was aged for 1 h at −78°C., and then ethyl trifluoroacetate (0.24 mL, 2.0 mmol) was added. Thereaction mixture was naturally warmed to room temperature, quenched withsaturated ammonium chloride, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(TEA:EtOAc:Hex 0.5:10:90 to 0.5:80:20) to afford 0.26 g of the productas a red solid.

2,2,2-Trifluoro-1-(5-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl)-2-(triisopropylsilyl)oxazol-4-yl)ethan-1-one(0.26 g, 0.44 mmol) was dissolved in THF (5 mL). The solution was cooledin an ice-water bath. Sodium borohydride (0.025 g, 0.66 mmol) in 0.5 mLof 0.5 N aqueous NaOH was added. The solution was stirred for 10 min,and then warmed to room temperature. The reaction was stirred untilcomplete. The reaction mixture was cooled in an ice-water bath, quenchedwith 1N aqueous HCl, stirred for 1 h, basified with saturated sodiumbicarbonate, and then extracted with ethyl acetate. The ethyl acetatephase was dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash chromatography using gradient elution(MeOH:TEA:EtOAc:Hex 0:2:25:75 to 5:2:25:75) to afford 0.20 g of TRV1667as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.03 (s, 1H), 7.24 (s, 1H),6.01 (s, 1H), 5.27 (q, J=6.19 Hz, 1H), 4.46 (t, J=7.53 Hz, 2H), 4.05 (t,J=6.78 Hz, 2H), 3.79 (broad, 1H), 3.74 (t, J=4.52 Hz, 4H), 3.12 (septet,J=6.90 Hz, 1H), 2.73 (t, J=7.53 Hz, 2H), 2.49 (t, J=4.14 Hz, 4H).

6-(6-methoxypyridin-3-yl)-4-fluorobenzo[c][1,2,5]oxadiazole (0.150 g,0.612 mmol) and 4-(azetidin-3-yl methyl) morpholine hydrochloride salt(0.140 g, 0.612 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.3 ml, 1.85 mmol) was added and mixture washeated at 80° C. overnight. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeproduct. Purification was done on ISCO flash chromatography system usingdichloromethane:methanol (95:5) as solvent to obtain6-(6-methoxypyridin-3-yl)-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole TRV1670 (0.218 g, 93%) as red color solid. ¹HNMR (CDCl₃, 400 MHz): δ 8.45 (d, J=4.0 Hz, 1H), 7.84 (d, J=4.0 Hz, 1H),7.82 (d, J=4.0 Hz, 1H), 7.10 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.98 (s,1H), 4.47 (t, J=8.0 Hz, 2H), 4.04 (m, 2H), 4.01 (s, 3H), 3.75 (m, 4H),3.13 (m, 1H), 2.74 (d, J=8.0 Hz, 2H), 2.48 (m, 4H).

Oxazole (0.50 mL, 7.60 mmol) was dissolved in anhydrous THF (20 mL). Thesolution was cooled in a dry ice/acetone bath. To the solution wasdropwise added n-BuLi (3.5 mL, 2.5 M, 8.8 mmol). After completeaddition, the solution was aged for 1 h at −78° C., and thentrimethylsilyl triflate (3.0 mL, 11.2 mmol) was added. The reactionmixture was naturally warmed to room temperature, quenched withsaturated ammonium chloride, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash chromatography using gradient elution(EtOAc:Hex 0:100 to 5:95) to give 1.36 g of 2-triisopropylsilyloxazole(79%).

2-Triisopropylsilyloxazole (0.45 g, 2.0 mmol) was dissolved in anhydrousTHF (10 mL). The solution was cooled in a dry ice/acetone bath. To thesolution was dropwise added n-BuLi (1.0 mL, 2.5 M, 2.5 mmol). Aftercomplete addition, the solution was aged for 1 h at −78° C., and then2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.6 mL, 2.94mmol) was added. The reaction mixture was naturally warmed to roomtemperature, quenched with saturated ammonium chloride, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was used directly used in the nextstep with further purification.

A reaction vial was charged with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazoleabove, 6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole (0.76 g, 2.0 mmol), Pd(PPh₃)₄ (0.070 g, 0.060mmol). After degassed and refilled with nitrogen, the vial was chargedwith dioxane (7.5 mL) and aq. Na₂CO₃ (4.0 mL, 2.0 M, 8.0 mmol). Thereaction vial was further re-degassed, refilled with nitrogen, sealed,and then heated to 95° C. until the reaction was complete. The mixturewas cooled to rt, worked up with 1N HCl, stirred for 1 h, and thenextracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (MeOH:TEA:EtOAc:Hex0:2:25:75 to 7.5:2:25:75) to afford 0.55 g (62% yield for two steps) of4-(3-(morpholinomethyl)azetidin-1-yl)-6-(oxazol-5-yl)benzo[c][1,2,5]oxadiazole as a red solid.

4-(3-(morpholinomethyl)azetidin-1-yl)-6-(oxazol-5-yl)benzo[c][1,2,5]oxadiazole (0.36 g, 1.06 mmol) was dissolved in anhydrousTHF (7.5 mL). The solution was cooled in a dry ice/acetone bath. To thesolution was dropwise added LDA (1.60 mL, 2.0 M, 3.20 mmol). Aftercomplete addition, the solution was aged for 1 h at −78° C., and thenethyl trifluoroacetate (0.54 mL, 4.54 mmol) was added. The reactionmixture was naturally warmed to room temperature, quenched with water,and re-cooled in an ice-water bath before sodium borohydride (0.17 g,4.54 mmol) was added. The solution was stirred for 10 min, and thenwarmed to room temperature and stirred until complete. The reactionmixture was cooled in an ice-water bath, quenched with 1N aqueous HCl,stirred for 1 h, basified with saturated sodium bicarbonate, and thenextracted with ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (MeOH:TEA:EtOAc:Hex0:2:25:75 to 7.5:2:25:75) to afford 0.27 g (a yield of 58%) of TRV 1677as an orange solid. ¹H NMR (CDCl₃, 400 MHz) δ=8.07 (s, 1H), 7.58 (d,J=7.03 Hz, 1H), 7.33 (s, 1H), 6.32 (s, 1H), 5.62-5.52 (m, 1H), 4.38 (t,J=8.28 Hz, 2H), 4.03-3.88 (m, 2H), 3.58 (t, J=8.28 Hz, 4H), 3.07(septet, J=6.78 Hz, 1H), 2.63 (t, J=7.53 Hz, 2H), 2.43-2.34 (m, 4H).

2,2,2-trifluoro-1-(2-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)oxazol-5-yl)ethan-1-ol(0.152 g, 0.5 mmol) and 4-(azetidin-3-ylmethyl) morpholine hydrochloridesalt (0.114 g, 0.5 mmol) were dissolved in Acetonitrile (5 ml) at roomtemperature, triethylamine (0.2 ml, 1.5 mmol) was added and mixture washeated at 50° C. overnight. After completion of reaction by TLC it wasquenched with Na2CO3 (2M) and extracted with EtOAC to give crudeTRV-1660. Purification was done on ISCO flash chromatography systemusing dichloromethane:methanol (95:5) as solvent to obtain 2, 2,2-trifluoro-1-(2-(7-(3-(morpholinomethyl) azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) oxazol-5-yl) ethan-1-ol TRV1686 (0.1400g, 68%) as orange color solid. ¹H NMR (DMSO, 400 MHz): δ 7.59 (s, 1H),7.53 (s, 1H), 7.36 (d, J=4.0 Hz, 1H), 6.45 (s, 1H), 5.57 (m, 1H), 4.41(t, J=8.0 Hz, 2H), 3.98 (m, 2H), 3.57 (m, 4H), 3.08 (m, 1H), 2.65 (d,J=8.0 Hz, 2H), 2.38 (m, 4H).

6-bromo-4-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazole(0.353 g, 1.0 mmol) was dissolved in dry THF (5 ml) and cooled to −78°C. under argon atm. 2.5M n-BuLi (0.48 ml, 1.2 mmol) was added drop wiseand mixture was allowed to stir for 20 min at −78° C.3-(benzyloxy)cyclobutan-1-one was then added to reaction mixture and wasstirred for additional 30 min and brought to rt followed by stirring foranother 30 min then it was quenched with ammonium chloride and extractedwith dichloromethane. Evaporation of solvent gave crude product whichwas purified on ISCO. to get Synthesis of3-(benzyloxy)-1-(7-(3-(morpholinomethyl)azetidin-1-yl)benzo[c][1,2,5]oxadiazol-5-yl) cyclobutan-1-ol TRV1692 (47%). ¹H NMR(CDCl₃, 400 MHz): δ 7.36 (m, 5H), 7.01 (s, 1H), 5.98 (s, 1H), 4.49 (s,2H), 4.40 (t, J=8.0 Hz, 2H), 3.98 (m, 2H), 3.94 (m, 1H), 3.73 (m, 4H),3.08 (m, 1H), 2.94 (m, 2H), 2.71 (d, J=8.0 Hz, 2H), 2.47 (m, 6H).

1, 4-Dibromobenzene (4.72 g, 20.00 mmol) was dissolved in anhydrous THF(50 mL) under argon. The solution was cooled to −78° C. and n-BuLi (2.5M, 8.8 mL, 20.5 mmol) was dropwise added. The solution was stirred at−78° C. for 0.5 h before oxetan-3-one (1.2 mL, 20.5 mmol) was added. Thesolution was stirred at −78° C. for 1 h, then quenched with saturatedaqueous ammonium chloride, and extracted with ethyl acetate. The organiclayer was washed with brine, dried with anhydrous sodium sulfate, andthen concentrated. The residue was purified by flash chromatographyusing gradient elution (EtOAc:Hex 10:90 to 50:50) to afford 3.94 g of3-(4-bromophenyl) oxetan-3-ol as a white solid (86% yield).

A reaction vial was charged with 3-(4-bromophenyl)oxetan-3-ol (1.72 g,7.5 mmol),4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(2.28 g, 8.64 mmol), Pd(PPh₃)₄ (0.26 g, 0.23 mmol). After degassed andrefilled with nitrogen, the vial was charged with dioxane (15 mL) andaq. Na₂CO₃ (10.0 mL, 2.0 M, 20.0 mmol). The reaction vial was furtherre-degassed, refilled with nitrogen, sealed, and then heated to 95° C.until it was complete. The mixture was cooled to rt, diluted with water,and then extracted with ethyl acetate. The ethyl acetate phase was driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby flash chromatography using gradient elution (EtOAc:Hex 10:90 to50:50) to afford 1.95 g (91% of yield) of34447-fluorobenzo[c][1,2,5]oxadiazol-5-yl)phenyl)oxetan-3-ol as a whitesolid.

3-(4-(7-Fluorobenzo[c][1,2,5]oxadiazol-5-yl)phenyl)oxetan-3-ol (0.43 g,1.50 mmol), 4-(piperidin-4-yl)morpholine (0.30 g, 1.80 mmol), Hunig'sbase (0.78 mL, 4.49 mmol) in MeCN (10 mL) was heated to 80° C.overnight. The reaction mixture was cooled to rt, diluted with water,and then extracted with ethyl acetate. The organic phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution(MeOH:TEA:EtOAC:Hex:0:2:25:75 to 5:2:25:75) to afford a total of 0.63 g(96% of yield) of TRV1717 as an orange solid. ¹H NMR (CDCl₃, 400 MHz)δ=7.75 (d, J=8.53 Hz, 2H), 7.69 (d, J=8.53 Hz, 2H), 7.35 (s, 1H), 6.59(s, 1H), 4.98 (d, J=7.03 Hz, 2H), 4.96 (d, J=7.03 Hz, 2H), 4.43 (d,J=12.80 Hz, 2H), 3.76 (t, J=4.65 Hz, 4H), 3.05 (dt, J₁=1.76 Hz, J₂=12.30Hz, 2H), 2.71 (broad, 1H), 2.62 (t, J=4.52 Hz, 4H), 2.49 (tt, J₁=1.76Hz, J₂=11.04 Hz, 1H), 2.05 (d, J=12.80 Hz, 2H), 1.78 (dq, J₁=3.51 Hz,J₂=12.05 Hz, 2H).

3-(4-(7-Fluorobenzo[c][1,2,5]oxadiazol-5-yl) phenyl) oxetan-3-ol (0.29g, 1.00 mmol), 4-(pyrrolidin-3-yl) morpholine (0.19 g, 1.20 mmol),Hunig's base (0.52 mL, 3.00 mmol) in MeCN (7.5 mL) was heated to 80° C.overnight. The reaction mixture was cooled to rt, diluted with water,and then extracted with ethyl acetate. The organic phase was dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash chromatography using gradient elution (MeOH:TEA:THF:Hex: 0:2:25:75to 5:2:25:75) to afford a total of 0.36 g (85% of yield) of TRV1719 asan orange solid. ¹H NMR (DMSO, 400 MHz) δ=7.84 (d, J=8.53 Hz, 2H), 7.71(d, J=8.53 Hz, 2H), 7.26 (s, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 4.81 (d,J=6.53 Hz, 2H), 4.71 (d, J=6.53 Hz, 2H), 4.05-3.92 (m, 2H), 3.75 (q,J=9.20 Hz, 1H), 3.61 (t, J=4.40 Hz, 4H), 3.52 (t, J=9.29 Hz, 1H), 3.00(pentet, J=7.91 Hz, 1H), 2.55-2.45 (m, 4H, overlap with DMSO peaks),2.31-2.22 (m, 1H), 1.91 (pentet, J=9.98 Hz, 1H).

1,4-Dibromobenzene (4.72 g, 20.00 mmol) was dissolved in anhydrous THF(50 mL) under argon. The solution was cooled to −78° C. and n-BuLi (2.5M, 8.8 mL, 20.5 mmol) was dropwise added. The solution was stirred at−78° C. for 0.5 h before oxetan-3-one (1.2 mL, 20.5 mmol) was added. Thesolution was stirred at −78° C. for 1 h, then quenched with saturatedaqueous ammonium chloride, and extracted with ethyl acetate. The organiclayer was washed with brine, dried with anhydrous sodium sulfate, andthen concentrated. The residue was purified by flash chromatographyusing gradient elution (EtOAc:Hex 10:90 to 50:50) to afford 3.94 g of3-(4-bromophenyl)oxetan-3-ol as a white solid (86% yield).

A reaction vial was charged with 3-(4-bromophenyl)oxetan-3-ol (1.72 g,7.5 mmol),4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(2.28 g, 8.64 mmol), Pd(PPh₃)₄ (0.26 g, 0.23 mmol). After degassed andrefilled with nitrogen, the vial was charged with dioxane (15 mL) andaq. Na₂CO₃ (10.0 mL, 2.0 M, 20.0 mmol). The reaction vial was furtherre-degassed, refilled with nitrogen, sealed, and then heated to 95° C.until it was complete. The mixture was cooled to rt, diluted with water,and then extracted with ethyl acetate. The ethyl acetate phase was driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby flash chromatography using gradient elution (EtOAc:Hex 10:90 to50:50) to afford 1.95 g (91% of yield) of34447-fluorobenzo[c][1,2,5]oxadiazol-5-yl)phenyeoxetan-3-ol as a whitesolid.

3-(4-(7-Fluorobenzo[c][1,2,5]oxadiazol-5-yl)phenyl)oxetan-3-ol (0.29 g,1.00 mmol), N-(4-piperidinyl)acetamide hydrochloride (0.22 g, 1.25mmol), Hunig's base (0.80 mL, 4.60 mmol) in MeCN (7.5 mL) was heated to100° C. for 48 h. The reaction mixture was cooled to rt, diluted withwater, and then extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by flash chromatography using gradient elution(MeOH:TEA:THF:Hex: 0:2:25:75 to 7.5:2:25:75) to afford a total of 0.25 g(82% of yield) of TRV1735 as a yellow solid. ¹H NMR (DMSO, 400 MHz)δ=7.89 (d, J=7.78 Hz, 1H), 7.86 (d, J=8.28 Hz, 2H), 7.73 (d, J=8.28 Hz,2H), 7.56 (s, 1H), 6.80 (s, 1H), 6.47 (s, 1H), 4.81 (d, J=6.78 Hz, 2H),4.71 (d, J=6.53 Hz, 2H), 4.31-4.21 (m, 2H), 3.90-3.78 (m, 1H), 3.24-3.11(m, 2H), 1.96-1.86 (s, 2H), 1.80 (s, 3H), 1.63-1.49 (m, 2H).

3-(4-(7-Fluorobenzo[c][1,2,5]oxadiazol-5-yl)phenyl)oxetan-3-ol (0.21 g,0.75 mmol), 4-(piperidin-4-ylmethyl)morpholine dihydrochloride (0.26 g,1.00 mmol), Hunig's base (0.80 mL, 4.60 mmol) in MeCN (7.5 mL) washeated to 100° C. for 48 h. The reaction mixture was cooled to rt,diluted with water, and then extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash chromatography using gradient elution(MeOH:TEA:THF:Hex:0:2:25:75 to 5:2:25:75) to afford a total of 0.30 g(88% of yield) of TRV1736 as an orange solid. ¹H NMR (DMSO, 400 MHz)δ=7.85 (d, J=8.28 Hz, 2H), 7.73 (d, J=8.28 Hz, 2H), 7.53 (s, 1H), 6.76(s, 1H), 6.47 (s, 1H), 4.81 (d, J=6.53 Hz, 2H), 4.71 (d, J=6.53 Hz, 2H),4.38-4.28 (m, 2H), 3.57 (t, J=4.40 Hz, 4H), 3.02 (t, J=12.30 Hz, 2H),2.43-2.25 (m, 4H), 2.18 (d, J=6.78 Hz, 2H), 1.92-1.77 (m, 3H), 1.37-1.25(m, 2H).

Biological Data

The following methodologies were used:

Preparation of Aβ₄₀ Stock Solutions

Aβ₄₀ (1.0 mg) was pre-treated in a 1.5 mL microfuge tube with HFIP (1mL) and sonicated for 20 min to disassemble any pre-formed Aβaggregates. The HFIP was removed with a stream of argon and the Aβdissolved in Tris base (5.8 mL, 20 mM, pH ˜10). The pH was adjusted to7.4 with concentrated HCl (˜10 μL) and the solution filtered using asyringe filter (0.2 μm) before being used.

Aβ₄₂ and tau proteins were prepared in an analogous manner as in theprocedure above.

ThT Aβ Aggregation Assay

The kinetic ThT assay for Aβ aggregation is similar to that of Chalifouret al (Chalifour et al, 2003, J. Biol. Chem. 278:34874-81). Briefly,pre-treated Aβ₄₀ or Aβ₄₂ (40 μM in 20 mM Tris, pH 7.4) was diluted withan equal volume of 8 μM Thioflavin T (ThT) in Tris (20 mM, pH 7.4, 300mM NaCl). Aliquots of Aβ/ThT (200 μL) were added to wells of a blackpolystyrene 96-well plate, followed by 2 μL of a compound in DMSO(variable concentration), or DMSO alone (controls). Incubations wereperformed in triplicate and were taken to contain 20 μM Aβ, variousconcentration of compound in 20 mM Tris, pH 7.4, 150 mM NaCl, 1% DMSO.Plates were covered with clear polystyrene lids and incubated at 37° C.in a Tecan Genios microplate reader.

ThS Tau Aggregation Assay

The kinetic ThS assay for tau aggregation generally follows the aboveprocedure, except that Thioflavin S (ThS) is used in place of ThT andtau protein is used in place of Aβ.

Analysis of ThT and ThS Aggregation Assays

Fluorescence readings (λex=450 nm, λem=480 nm) were taken every 15 min.,after first shaking at high intensity for 15 s and allowing to settlefor 10 s before each reading. Active compounds attenuated the increasein fluorescence over time that occurred in controls. In FIGS. 1-7, thetime this procedure was performed extended to 80 hours (rightmost partof X-axis), at which point fluorescence increase generally reached anasymptote. Applying a definition of DMSO control at 80 hr as 100%aggregation (0% inhibition) and DMSO control at 0 hr as 0% aggregation(100% inhibition), a % inhibition score where higher is better can becalculated for a given concentration of compound. By repeating thisprocedure over several concentrations, a mean inhibitory concentration(IC₅₀) can be measured, as is given in the table below for somecompounds.

Aβ42 Biotinylated Assay

Terminally biotinylated beta-amyloid (biotin-AB) was dissolved in HFIPat the concentration of 1 mg/ml and aliquoted to 50 μl/tube in 0.65 mlcolored microfuge tubes (Fisher 02-681-248). The aliquots were dilutedimmediately by adding 450 μl of HFIP to 0.1 mg/ml. Approximately 46 ul(containing approximately 4.6 ug of biotin-AB) were taken from a tube,100 ul of HFIP added, vortexed, and dried to a thin film under an N₂stream. 100 μl of trifluoroacetic acid (TFA) was added and vortexed.After 10 minute incubation at room temperature in a hood, resulting indisaggregation of seeds, the sample was vortexed again and dried againto a thin film under an N₂ stream. 100 μl of HFIP was added, mixed, andthe biotin-AB sample was dried for a third time under an N₂ stream toremove residual TFA. The treated biotin-AB was dissolved in DMSO to afinal peptide concentration of 2.3 μg/ml (SOX).

An ELISA “capture” plate (Costar 9018) was coated with 50 μl of 1 μg/mlNeutrAvidin™ (NA) in 10 mM sodium phosphate buffer, pH 7.5. (NeutrAvidincan be prepared as 1 mg/ml (1000×) in milliQ water/10% glycerol andstored at −80° C. before use.) The plate was sealed plate with adhesivefilm and stored at 4° C. overnight, then blocked for 2 hours (unsealed)at room temperature with 200 μl/well OFB+0.1% v/v Tween 20. The“capture” plate was allowed to come to room temperature.

Several dilutions of test compound were prepared with 100% DMSO,according to the desired concentration to be tested. 2.5 μl of dilutedtest compound was pipetted into the bottom of each well of a 96-well“dilution” polypropylene plate (Costar 3365), to which was added 250 ulof Oligomer Formation Buffer (OFB: 20 mM sodium phosphate, pH 7.5-150 mMNaCl). To begin oligomerization, 2 μl/well of the biotin-AB was added tothe bottom of each well of a 96-well “reaction” polypropylene plate(Costar 3365) and 100 ul of each well of the “dilution” plate wastransferred to the “reaction” plate (final concentration of DMSO beingup to 1%). The reaction plate was sealed and incubated for 1 hr at roomtemperature without shaking. The reaction was then stopped by theaddition of 50 ul of 0.3% Tween 20 in water.

The “capture” plate blocking solution was removed, and 50 ul of eachwell of the “reaction” plate was transferred to each well of the“capture” plate. The “capture” plate was sealed and incubated for 2hours at room temperature with shaking at 150 rpm. The “capture” platewas then washed on a plate washer (3×) with 200 ul/well TBST (20 mMTris-HCL, pH 7.5/150 mM NaCl/0.1% Tween 20). 50 ul ofStreptavidin-horseradish protein (1:20,000 dilution) in OFB+0.1% Tween20 was added to each well, the “capture” plate was sealed and incubatedfor 1 hr with shaking at 150 rpm. As before, the plate was washed, then100 ul of TMB/H2O2 substrate solution was added to each well. After 5-10minutes, 100 ul of 1% v/v sulfuric acid was added and the absorbance ofeach well was read at 450 nm using a standard plate reader.Data is summarized in the table below; numbers given in parenthesis forthe Aβ 40 Thioflavin T assays are the values in that particularexperiment for compound ID 1027, given as the first entry in this tablefor structural comparison. “IC50 Aβ42-bio” column refers to theapproximate value of the Aβ42 biotinylated assay IC₅₀ in micromoles/L.

IC50 % inhib. % inhib % inhib % inhib IC50 Thioflavin Thioflavin TThioflavin T Thioflavin T Thioflavin T Aβ T Aβ 40 Aβ 40 Aβ 40 Aβ 40 42-ID Structure A β 1-40 (20 μM) 10 μM (5 μm) (3 μm) bio 1027

1259

66.34 (66.24) 1310

81.54 (64.67) 1358

72.72 (67.72) 1359

75.19 (67.72) 1360

58.91 (67.72) 1361

88.94 (67.72) 1362

41.36 (65.29) 1364

1.00 (10.47) 1365

0.92 (10.47) 1366

3.03 (10.47) 1368

61.43 (53.47) 1376

51.7 (14.7) 1377

1.86 (22.1) 1378

2.38 (22.1) 1379

1.65 (22.1) 1380

57.10 (55.8) 1381

70.36 (55.78) 1382

60.02 (55.78) 1383

54.94 (55.78) 1384

72.39 (55.78) 1385

65.63 (55.78) 1387

5.76 78 (69) 52 (56) 40 (38) 1390

75 (69) 51 (48) 1392

69(53) 36 (28) 1397

61(53) 38(28) 1400

80 (58) 48 (34) 1401

58 (58) 39 (34) 1403

81 (58) 51 (34) 1404

69 (52) 39 (28) 1405

76 (52) 46 (28) 1406

83 (52) 53 (28) 1409

69 (52) 50 (28) 1411

81 (53) 56(28) 1412

64(53) 51(28) 1413

61.3(53) 53(28) 1414

69(53) 53(28) 1415

53 (51) 52 (33) 1417

75 (51) 52 (33) 1418

55 (51) 34 (33) 1419

55 (51) 48 (33) 1420

48 (51) 44 (33) 1427

41 (38) 18 (18) 1428

78 (47) 52 (26) 1432

51 (47) 23 (26) 1435

66 (50) 52 (34) 1436

67 (50) 48 (33) 1437

50 (50) 44 (33) 1440

60 (50) 52 (33) 1441

64 (50) 47 (33) 1442

43 (50) 29 (33) 1446

50 (50) 29 (36) 1447

70 (50) 54 (36) 1448

55 (50) 45 (36) 1449

72 (50) 55 (36) 1450

79 (50) 57 (36) 1451

73 (56) 54 (38) 1452

63(47) 50(23) 1455

60(47) 41(23) 1456

64(47) 36(23) 1457

65(47) 51(23) 1459

62 (56) 47 (38) 1460

44 (56) 36 (38) 1461

71.7 (46.8) 58.9 22.9 1462

48 (56) 53 (38) 1463

61 (51) 37 (50) 1464

35 (51) >20 1465

62 (64) 44 (42) >20 1466

49 (64) 37 (42) 4.1 1467

43 (64) 28 (42) 5.1 1468

65 (64) 44 (42) 2.4 1469

75 (55) 70 (50) 2.4 1470

62 (55) >20 1471

29 (55) 4.4 1472

65 (55) 3.6 1473

31 (55) 18.1 1474

77 (55) 3.1 1476

36 (55) 12.2 1477

30 (51) 1.83 1478

63 (61) 1.82 1479

24 (51) 7.94 1480

31 (51) 6.33 1481

11 (51) 6.14 1482

41 (51) 5.52 1483

36 (51) 8.21 1484

56 (61) 6.5 1485

26 (61) 2.63 1486

32 (61) 19.7 1487

33 (61) 0.62 1488

31 (61) 8.69 1489

34 (61) 1.6 1490

27 (61) 4.4 1491

32 (61) 0.52 1492

22 (61) 4.8 1493

57 (61) 12.9 1494

45 (62) 2.01 1495

64 (61) 5.91 1496

41 (61) 13.5 1497

65 (61) >20 1498

48 (61) 10.8 1499

34 (57) 23.3 1500

51 (57) >20 1501

48 (57) >20 1502

55 (57) 4.78 1503

33 (57) >20 1504

72 (67) 5.27 1505

62 (57) 4.62 1506

44 (61) 4.44 1507

83 (69) 2.46 1509

71 (69) >20 1510

65 (69) >20 1511

27 (69) 21.3 1512

77 (69) 12.0 1514

57 (69) 11.2 1515

61 (69) 16.7 1516

47 (69) >20 1517

33 (69) 6.8 1518

35 (69) >20 1519

53 (69) 8.2 1520

46 (69) 6.1 1521

20 (70) 30.1 1522

44 (70) 10.1 1523

55 (73) 1.3 1524

61 (73) 14.9 1525

63 (73) 13.2 1526

60 (73) 5.8 1527

49 (73) 7.5 1528

50 (73) 7.8 1529

74 (73) 9.0 1530

79 (73) 10.5 1531

45 (73) 2.7 1532

68 (73) 27.1 1533

35 (73) 5.6 1534

67 (77) 3.5 1535

77 (78) 71 (59) 2.9 1536

61 (78) 43 (59) 4.2 1537

74 (78) 71 (59) 3.5 1538

54 (78) 47 (59) 2.9 1539

55 (78) 53 (59) 7.8 1540

50 (78) 41 (59) 1.8 1541

31 (68) 19 (53) 4.0 1542

36 (68) 15 (53) >20 1543

84 (68) 63 (53) 1.1 1544

NA NA 3.9 1545

NA NA 8.4 1546

NA NA 8.4 1547

NA NA 12.0 1548

NA NA 25.3 1549

NA NA 5.5 1550

NA NA 5.3 1551

NA NA 6.8 1552

NA NA 5.7 1553

NA NA 12.1 1554

NA NA 8.3 1555

NA NA 5.0 1556

NA NA 6.6 1557

NA NA 18.7 1558

NA NA 5.9 1559

NA NA 7.6 1560

NA NA 6.7 1561

NA NA 6.9 1562

2.7 1563

>20 1564

6.0 1565

>20 1566

>20 1567

26.9 1568

5.5 1569

11.5 1570

>20 1571

>20 1572

>20 1573

12.9 1574

16.5 1575

4.0 1576

46.0 1577

14.8 1578

2.9 1579

96.0 1580

>20 1584

7.0 1585

5.8 1586

41.9 1587

12.3 1588

30.2 1592

15.1 1594

>20 1597

7.5 1598

9.9 1599

1600

1606

>20 1607

>20 1608

8.6 1609

2.4 1610

>20 1611

>20 1612

>20 1613

>20 1615

>20 1616

16.2 1617

14.6 1618

4.98 1619

11.3 1620

11.1 1621

16.7 1622

5.8 1625

4.2 1626

10.9 1627

10.4 1628

33.1 1629

15.7 1636

10.3 1638

3.0 1639

3.2 1643

14.2 1645

>20 1647

14.7 1651

30.1 1658

>20 1659

12.4 1660

3.9 1663

>20 1665

21.8 1666

>20 1667

17.5 1670

11.2 1677

26.1 1692

5.6 1717

22.6 1719

13.0 1735

2.4 1736

9.7

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, in which R₁₁ is selectedfrom the group consisting of 4-(pyrrolidin-1-yl)piperidin-1-yl,N-methyl-3-(pyrrolidin-1-yl)propan-1-amino,N¹,N¹,N³-trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino,3-(pyrrolidin-1-ylmethyl)azetidin-1-yl, 3-(pyrrolidin-1-ylmethanon)azetidin-1-yl, 3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl,3-(morpholin-1-ylmethyl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl, 3-(methylsulfonamide-N-methyl)azetidin-1-yl, 3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl) azetidin-1-yl; R₁₃ is selected from the groupconsisting of 3-(benzyloxy)-1-methylcyclobutan-1-ol-1-yl, oxazoleoptionally substituted with one or more of substituents A, oxadiazoleoptionally substituted with one or more of substituents A, phenyloptionally substituted with one or more of substituents A, thiopheneoptionally substituted with one or more of substituents A, thiazoleoptionally substituted with one or more of substituents A, furanoptionally substituted with one or more of substituents A, pyrazoleoptionally substituted with one or more of substituents A,N-methylpyrazole optionally substituted with one or more of substituentsA, 2-pyridine optionally substituted with one or more of substituents A,3-pyridine optionally substituted with one or more of substituents A,and 4-pyridine optionally substituted with one or more of substituentsA, where A is selected from the group consisting of alkyl, alkoxy,alkthiolyl, isopropyl, t-butyl, trifluoromethyl, chloro, cyano, CF₃O—,methanonyl, methylsulfonyl, trifluoromethylsulfonyl, amide (connected ineither direction) optionally substituted with one or more alkyl, —CH₂OH,1-ol-2,2,2-trifluoroethan-1-yl, oxetan-3-ol-3-yl, 2-ol-propan-2-yl, andcyclopropyl; and R₁₂ and R₁₄ are each independently hydrogen or alkyl;with the proviso that if A is 1-ol-2,2,2-trifluoroethan-1-yl, then itcannot be connected to phenyl or thiophene.
 2. The compound of claim 1or a pharmaceutically acceptable salt thereof, in which R₁₁ is selectedfrom the group consisting of 4-(pyrrolidin-1-yl)piperidin-1-yl,N-methyl-3-(pyrrolidin-1-yl)propan-1-amino,N¹,N¹,N³-trimethylpropane-1,3-diamino, N,N-dimethylpiperidin-4-amino,3-(pyrrolidin-1-ylmethyl)azetidin-1-yl,3-(pyrrolidin-1-ylmethanon)azetidin-1-yl,3-(morpholin-1ylmethyl)pyrrolidin-1-yl, and3-(morpholin-1-ylmethyl)azetidin-1-yl; and R₁₃ is selected from thegroup consisting of phenyl optionally substituted with one or more ofsubstituents A, thiophene optionally substituted with one or more ofsubstituents A, thiazole optionally substituted with one or more ofsubstituents A, furan optionally substituted with one or more ofsubstituents A, pyrazole optionally substituted with one or more ofsubstituents A, N-methylpyrazole optionally substituted with one or moreof substituents A, 2-pyridine optionally substituted with one or more ofsubstituents A, 3-pyridine optionally substituted with one or more ofsubstituents A, and 4-pyridine optionally substituted with one or moreof substituents A, where A is selected from the group consisting ofalkyl, alkoxy, alkthiolyl, isopropyl, t-butyl, trifluoromethyl, chloro,cyano, CF₃O—, methanonyl, methylsulfonyl, trifluoromethylsulfonyl, amide(connected in either direction) optionally substituted with one or morealkyl, and —CH₂OH.
 3. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, in which R₁₁ is selected from the groupconsisting of 3-(morpholin-1-ylmethyl)azetidin-1-yl,3-(2-ethanolamino-N-methyl)azetidin-1-yl,3-(morpholin-1-yl)pyrrolidin-1-yl, 4-(ethylamido)piperidin-1-yl,3-(aminomethyl)azetidin-1-yl, 4-(morpholin-1-yl)piperidin-1-yl,4-(morpholin-1-ylmethyl)piperidin-1-yl, 3-amidoazetidin-1-yl,3-(propan-2-ol-2-yl)azetidin-1-yl,3-(methylsulfonamide-N-methyl)azetidin-1-yl,3-(methylamido-N-methyl)azetidin-1-yl, and3-(methylamino-N-methyl)azetidin-1-yl; and R₁₃ is selected from thegroup consisting of 3-(benzyloxy)-1-methylcyclobutan-1-ol-1-yl, oxazoleoptionally substituted with one or more of substituents A, oxadiazoleoptionally substituted with one or more of substituents A, and3-pyridine optionally substituted with one or more of substituents A,where A is selected from the group consisting of1-ol-2,2,2-trifluoroethan-1-yl, oxetan-3-ol-3-yl, 2-ol-propan-2-yl, andcyclopropyl; with the proviso that if A is1-ol-2,2,2-trifluoroethan-1-yl, then it cannot be connected to phenyl orthiophene.
 4. The compound of claim 3 or a pharmaceutically acceptablesalt thereof, in which R₁₃ is selected from the group consisting of5-(2-ol-propan-2-yl)oxadizol-3-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-5-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-2-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)thiazol-2-yl,4-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-6-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)-pyridin-6-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-2-yl,5-(1-ol-2,2,2-trifluoroethan-1-yl)oxazol-3-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-5-yl,3-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-2-yl,3-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-6-yl,2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl, and2-(1-ol-2,2,2-trifluoroethan-1-yl)thiophen-4-yl.
 5. The compound ofclaim 4 or a pharmaceutically acceptable salt thereof, in which R₁₁ is3-(morpholin-1-ylmethyl)azetidin-1-yl and R₁₃ is selected from the groupconsisting of 2-(1-ol-2,2,2-trifluoroethan-1-yl)pyridin-3-yl and5-(2-ol-propan-2-yl)oxadizol-3-yl.
 6. A method of treatment of anamyloid disease in a subject comprising administering a therapeuticallyeffective amount of a compound of any of claims 1-5 to the subject. 7.The method of claim 6 in which the amyloid disease is Alzheimer'sdisease.
 8. The method of claim 6 in which the amyloid disease isParkinson's disease.
 9. The method of claim 6 in which the amyloiddisease is frontotemporal dementia.
 10. The method of claim 6 in whichthe amyloid disease is progressive supranuclear palsy.
 11. The method ofclaim 6 in which the amyloid disease is type 2 diabetes mellitus.
 12. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 13. A method for treating acondition which is a member selected from loss of memory, loss ofcognition and a combination thereof, said method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of claim
 1. 14. The method according to claim 13,wherein said condition is associated with Alzheimer's disease.
 15. Themethod according to claim 13, wherein a total daily dose of from about0.0003 to about 50 mg/kg of body weight is administered.
 16. Apharmaceutical composition comprising a compound of claim 2 and apharmaceutically acceptable carrier.
 17. A pharmaceutical compositioncomprising a compound of claim 3 and a pharmaceutically acceptablecarrier.
 18. A pharmaceutical composition comprising a compound of claim4 and a pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition comprising a compound of claim 5 and a pharmaceuticallyacceptable carrier.
 20. A method for treating a condition which is amember selected from loss of memory, loss of cognition and a combinationthereof, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of claim 4.